Endothelial Dysfunction Therapy Agents

Abstract

This invention proposes compounds of formula IA, IB, IC, ID, IE, IF, IG, IH, or IJ for the treatment or prevention of the following vascular endothelial dysfunction or vascular leakage diseases:

Description

Technical Field

[0001] This invention relates to a novel therapeutic agent for vascular endothelial dysfunction. Background Technology

[0002] Vascular endothelial cells are cells that line the lumen of blood vessels. Recent findings have revealed that these cells play a crucial role not only in selectively regulating the permeability of substances entering and leaving the vascular system, but also in blood pressure regulation and antithrombotic functions.

[0003] Disruption of the vascular endothelial barrier, leading to increased vascular permeability, is associated with numerous pathological conditions, including various inflammatory diseases, cardiovascular diseases, acute lung injury, kidney disease, and retinal diseases. In particular, dysfunction of vascular endothelial cells reduces nitric oxide production in these cells, thereby impairing the regulation of vasodilation and vasoconstriction. This dysfunction is known to cause hypertension and contribute to a wide range of diseases, such as heart failure, dyslipidemia, atherosclerosis, hyperlipidemia, diabetes, retinal diseases, macular degeneration, heart disease, coronary artery disease, kidney failure and kidney disease, chronic obstructive pulmonary disease (COPD), cerebrovascular diseases including dementia, erectile dysfunction, and metabolic syndrome.

[0004] Endothelial dysfunction is also associated with diseases primarily caused by vascular leakage due to impaired vascular integrity. Therefore, by inhibiting endothelial cell damage, endothelial cell death can be suppressed, vascular leakage can be blocked, the integrity of the vascular wall structure can be enhanced, and the intercellular stability of blood vessels can be improved, thereby preventing or treating diseases related to endothelial cell dysfunction and vascular leakage.

[0005] Specifically, disruption of the vascular endothelial barrier, which leads to increased vascular permeability, can cause various pathological processes, such as various inflammatory diseases, acute lung injury, and diabetic retinopathy.

[0006] Endothelial permeability is tightly regulated by cell-cell junctions between adjacent vascular endothelial cells, including adhesion junctions (AJ) and tight junctions (TJ). TJs are composed of various proteins, such as closure proteins, sealing proteins, junction adhesion molecules (JAM), and occluder band proteins (ZO). Closure proteins, sealing proteins, and JAM are key transmembrane proteins with connective properties, facilitating the formation of a tight seal between the opposing endothelial membranes of adjacent cells. Closure proteins and sealing proteins form homodimeric bridges, while ZO and cingulin connect these transmembrane proteins to actin filaments.

[0007] The earliest symptom of diabetic retinopathy is leakage from retinal blood vessels due to disruption of the blood-retinal barrier (BRB), leading to retinal edema and vascular endothelial cell proliferation. The BRB is a selectively permeable vascular endothelial barrier formed by well-differentiated microvessels in the eye.

[0008] BRB destruction occurs in the early stages of retinopathy and can be reversed before irreversible neovascularization occurs in proliferative vascular retinopathy. VEGF plays a key role in BRB destruction by altering the integrity of tight junctions and the structured vascular endothelial cell cytoskeleton, and BRB destruction increases permeability during the onset of diabetic retinopathy (DR).

[0009] US Patent 9,353,144B2 discloses a compound SAC-1004 (also known as CU06-1004) as a vascular leakage blocker, which is a therapeutic agent for treating vascular endothelial cell dysfunction.

[0010] The inventors have synthesized a novel compound with a novel structure that can block vascular leakage and treat vascular endothelial dysfunction, and hereby disclose the compound in this specification. Summary of the Invention

[0011] Technical issues

[0012] Therefore, the object of the present invention is to provide compounds for the prevention or treatment of vascular endothelial dysfunction or vascular leakage diseases.

[0013] Problem-solving methods

[0014] To achieve the above objectives, this disclosure provides compounds, their stereoisomers, or pharmaceutically acceptable salts thereof represented by the following chemical formulas IA, IB, IC, ID, IE, IF, IG, IH, or IJ:

[0015] .

[0016] The dashed lines represent single bonds or bonds that do not exist.

[0017] Y represents H and C. 1-6 Alkyl, -C(=O)(R 1 ) or -P(= O)(R 2 (R³);

[0018] R 1 To R 3 Each independently is C 1-6 Alkyl or phenyl;

[0019] X is H or C 1-6 alkyl;

[0020] R is -C n Alkylene-LMR 4 ;

[0021] n is an integer from 0 to 10, and -C nAlkyl groups may optionally contain carbon-carbon double bonds;

[0022] L is C (= O) or CH2;

[0023] M represents O, S, N (R) 5 (or may not exist;)

[0024] R 4 C is H, unsubstituted, or substituted with one or more halogens. 1-6 Alkyl, unsubstituted 3- to 10-membered cycloalkyl or one or more halogen-substituted 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocycloalkyl, -C (= O)(R 6 ) or -S(= O)2(R 7 );

[0025] R 5 For H or C 1-6 alkyl;

[0026] R 6 and R 7 Each independently is C 1-6 alkyl;

[0027] V is H or C 1-6 Alkyl, under the condition that

[0028] Compounds are not .

[0029] Effects of the present invention

[0030] The compounds of this invention provide excellent cell death inhibition and LDH release reduction effects, inhibit changes in cell junction proteins, and suppress cell permeability, and therefore can be used to treat vascular leakage-related diseases or vascular endothelial dysfunction.

[0031] Brief description of the attached figures

[0032] Figures 1a to 1o This demonstrates the excellent inhibitory effect on cell death provided by several exemplary compounds according to the present invention.

[0033] Figures 2a to 2o This demonstrates the protective effect of several exemplary compounds according to the present invention against morphological changes in vascular endothelial cells.

[0034] Figures 3a to 3o The concentration-dependent inhibition of cell death provided by several exemplary compounds according to the present invention under serum-free culture conditions is demonstrated.

[0035] Figures 4a to 4o The concentration-dependent inhibition of LDH release provided by several exemplary compounds according to the present invention is shown under serum-free culture conditions.

[0036] Figure 5 The images displayed are fluorescence microscopy images showing the inhibitory effect of several exemplary compounds according to the invention on the destabilization of VE-cadherin after VEGF treatment.

[0037] Figure 6 The expression levels of the linker proteins are shown, demonstrating the inhibitory effect of several exemplary compounds according to the invention on the destabilization of VE-cadherin after VEGF treatment.

[0038] Figure 7 Display according to Figure 6 The result is the number of VE-cadherin lines, i.e., the Nb fragment value.

[0039] Figure 8 Display according to Figure 6 The total length of the VE-cadherin lines was obtained as a result.

[0040] Figures 9a to 9e The results of TEER analysis show the inhibitory effect of several exemplary compounds according to the present invention on cell permeability.

[0041] Figures 10a to 10e The results of FITC leakage analysis show the inhibitory effect of several exemplary compounds according to the present invention on cell permeability.

[0042] Figure 11 This demonstrates a significant improvement in object recognition capability provided by several exemplary compounds according to the present invention (*: p<0.05; G1 vs G2). Compounds A, B, and C refer to the compounds of Synthetic Examples 1-10, CU06-1004, and Synthetic Examples 2-3, respectively.

[0043] Figure 12 This demonstrates the superior improvement in memory performance provided by several exemplary compounds according to the present invention (*: p<0.05; G1 vs G2; #: p<0.05; G2 vs all groups). Compounds A, B, and C refer to the compounds of Synthetic Examples 1-10, CU06-1004, and Synthetic Examples 2-3, respectively.

[0044] Figure 13a and 13bThe graph shows the accumulation of amyloid β (Aβ) plaques in the hippocampus (HIP) after treatment with several exemplary compounds according to the present invention (***: p < 0.001; G1 vs. G2; #: p < 0.05, ##: p < 0.01, ###: p < 0.001; G2 vs. all groups). Compounds A, B, and C refer to the compounds of synthetic Examples 1-10, CU06-1004, and synthetic Examples 2-3, respectively.

[0045] Figure 13c and 13d The graph shows the accumulation of amyloid β (Aβ) plaques in the prefrontal cortex (PFC) after treatment with several exemplary compounds according to the present invention (***: p < 0.001; G1 vs. G2; #: p < 0.05, ##: p < 0.01, ###: p < 0.001; G2 vs. all groups). Compounds A, B, and C refer to the compounds of synthetic Examples 1-10, CU06-1004, and synthetic Examples 2-3, respectively.

[0046] Figures 14a to 14c The graph shows the expression levels of ZO-1 after treatment with several exemplary compounds according to the present invention (**: p < 0.01; G1 vs. G2; ##: p < 0.01; G2 vs. all groups). Compounds A, B, and C refer to compounds from Synthetic Examples 1-10, CU06-1004, and Synthetic Examples 2-3, respectively.

[0047] Figure 14d and 14e The graph shows the expression levels of Claudin-5 after treatment with several exemplary compounds according to the present invention (*: p < 0.05; G1 vs. G2; #: p < 0.05; G2 vs. all groups). Compounds A, B, and C refer to the compounds of synthetic Examples 1-10, CU06-1004, and synthetic Examples 2-3, respectively.

[0048] Figure 15a and 15b The graph shows the expression levels of RAGE after treatment with several exemplary compounds according to the present invention (***: p < 0.01; G1 vs. G2; ##: p < 0.01, ###: p < 0.001; G2 vs. all groups). Compounds A, B, and C refer to the compounds of synthetic Examples 1-10, CU06-1004, and synthetic Examples 2-3, respectively.

[0049] Figures 16a-16dThe graph shows the expression levels of GFAP after treatment with several exemplary compounds according to the present invention (***: p < 0.01; G1 vs. G2; #: p < 0.05, ###: p < 0.001; G2 vs. all groups). Compounds A, B, and C refer to compounds from synthetic examples 1-10, CU06-1004, and synthetic examples 2-3, respectively.

[0050] Figure 17a and 17b The graph shows the expression levels of Iba1 after treatment with several exemplary compounds according to the present invention (***: p < 0.01; G1 vs. G2; ###: p < 0.001; G2 vs. all groups). Compounds A, B, and C refer to the compounds of synthetic Examples 1-10, CU06-1004, and synthetic Examples 2-3, respectively. Detailed Implementation

[0051] This invention provides a novel vascular leakage blocking agent, namely, a compound represented by the following chemical formula I:

[0052]

[0053] Formula I can be a compound of the following formula:

[0054]

[0055] Formula I (including Formulas IA, IB, IC, ID, IE, IF, IG, IH, and IJ) is defined as follows.

[0056] In the definitions described below, the scope of Equation I is determined by combining the definitions of its constituent elements. In forming such a combination, each constituent element defines multiple alternatives, any one of which can be selected and combined to define the structure.

[0057] In this formula, dashed lines represent single bonds or bonds that do not exist, and lines with dashed borders represent double bonds or single bonds. When lines represent single bonds, it is clear that formula I can exist in the form of diastereomers as shown below, with the remainder of formula I omitted:

[0058]

[0059] Y is independently selected from H and C. 1-6 Alkyl, -C (= O) (R 1 ) and -P (= O) (R 2 ) (R 3 It can also be selected from one or more of the foregoing combinations. The two Y groups can be the same or different;

[0060] R 1 To R 3 Each independently is C 1-6 Alkyl or phenyl;

[0061] X is selected from H and C. 1-6 Alkyl groups, and may also be selected from one or more of the foregoing in any combination;

[0062] R is -C n Alkylene-LMR 4 The condition is

[0063] n can be selected from integers 0 to 10, 0 to 9, 0 to 8, 0 to 7, 0 to 6, 0 to 5, 0 to 4, and 0 to 3;

[0064] -C n Alkyl groups may optionally contain carbon-carbon double bonds;

[0065] L is selected from C (= O) and CH2, and may also be selected from one or more of the above in any combination;

[0066] M is selected from O, S, N (R) 5 ), or does not exist, and can also be selected from O, S, N (R 5 Any combination of one or more of the following;

[0067] R 4 Selected from H, unsubstituted or one or more halogen-substituted C 1-6 Alkyl, unsubstituted 3-10 membered cycloalkyl or one or more halogen-substituted 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered heterocycloalkyl, –C (= O)(R 6 ) and -S(= O)2(R 7 Furthermore, it can be selected from one or more of the above, or any combination thereof;

[0068] R 5 Selected from H and C 1-6 Alkyl groups, and may also be selected from any combination of one or more of the foregoing;

[0069] R 6 and R 7 Each independently is C 1-6 alkyl;

[0070] V is H or C 1-6 Alkyl groups; and

[0071] This compound does not include The condition is C 1-6 Alkyl groups can be selected from C 1-5 Alkyl, C 1-4Alkyl, C 1-3 Alkyl, C 1-2 A substitution for alkyl and C1 alkyl;

[0072] The 3- to 10-membered cycloalkyl group can be replaced by a 3- to 7-membered cycloalkyl group, a 3- to 6-membered cycloalkyl group, or a 9- to 10-membered cycloalkyl group;

[0073] 5- to 10-membered heteroaryl groups can be replaced by 5- to 6-membered heteroaryl groups or 9- to 10-membered heteroaryl groups;

[0074] 3- to 10-membered heterocyclic alkyl groups can be replaced by 5- to 10-membered heterocyclic alkyl groups, 5- to 6-membered heterocyclic alkyl groups, or 9- to 10-membered heterocyclic alkyl groups; and

[0075] C 3-12 Alkyl groups can be C 5-12 Alkyl, C 6-12 Alkyl or C 6-10 Alkyl substitution.

[0076] Unless otherwise stated, the terms "alkylene" and "alkyl" as used herein include saturated hydrocarbon groups that can be straight-chain or branched. For example, "C 1-6 "Alkyl" refers to an alkyl group having a carbon backbone consisting of 1-6 carbon atoms. Specifically, C 1-6 Alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, tert-pentyl, secondary-pentyl, neopentyl, and hexyl. The term "C6 alkyl" refers to a fully saturated hydrocarbon group containing six carbon atoms, including its structural isomers. The term "alkyl" indicates a monovalent substituent, while "alkylene" indicates a divalent substituent.

[0077] Unless otherwise stated, the term "cycloalkyl" as used herein refers to a saturated hydrocarbon residue or a cycloalkyl residue included in a ring structure. The term "C" 3-10 "Cycloalkyl" or "3-10 membered cycloalkyl" refers to a cycloalkyl hydrocarbon residue containing 3-10 carbon atoms as ring members. The hydrocarbon residue includes monocyclic, bicyclic, or tricyclic rings containing two or three rings, and the two or three rings can form bridged, fused, or spirocyclic cycloalkyl groups. Examples of 3-10 membered cycloalkyl groups include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, and decahydronaphthyl.

[0078] Unless otherwise stated, the term "heterocyclic alkyl" refers to a monovalent saturated residue comprising one to three rings containing one or more heteroatoms selected from N, O, or S (e.g., 1 to 5, 1 to 4, 1 to 3, 1 to 2, or 1 heteroatom). The heterocyclic alkyl may be monocyclic or a bicyclic or tricyclic structure comprising two or three rings, wherein the two or three rings can form a bridged, fused, or spirocyclic heterocyclic alkyl. When a heterocyclic alkyl consists of multiple rings, heteroatoms may be present in all rings or only in some rings. When the type of heteroatom is specifically limited, only specific heteroatoms are included.

[0079] The term "3 to 10-membered heterocyclic alkyl" refers to a heterocyclic alkyl group containing 3 to 10 ring atoms.

[0080] The term "aryl" refers to an aromatic group having a monocyclic or fused ring of two or three hydrocarbon aromatic rings. 6-10 aryl groups refer to aromatic ring compounds containing 6-10 carbon atoms and may include phenyl and naphthyl groups.

[0081] Unless otherwise specified, the term "heteroaryl" refers to an aromatic group containing one or more aromatic rings (with the remaining ring atoms being carbon), wherein the aromatic group contains one or more heteroatoms selected from N, O, or S (e.g., 1 to 4, 1 to 3, 1 to 2, or 1 heteroatom) as ring atoms, and includes monocyclic or fused rings having two or three rings. When the type of heteroatom is specifically limited, only the specified heteroatom is included as a ring atom. When a heteroaryl consists of multiple rings, the heteroatom may be present in all rings or only in some rings. When the type of heteroatom is specifically limited, only the specific heteroatom is included. The term "5-10-membered heteroaryl" refers to a heteroaryl containing 5-10 ring atoms.

[0082] The term "halogen" refers to a halogen atom such as F, Cl, Br, or I, where, when one or more halogen atoms are substituted, the number of substituted halogen atoms can be selected from 1 to 5, 1 to 4, 1 to 3, 1 to 2, or 1. Compounds of Formula I according to the invention include their stereoisomers, solvates, hydrates, and pharmaceutically acceptable salts.

[0083] Unless otherwise specifically defined and contradictory, the term "compound" means all compounds of formula I and is used to include their stereoisomers, solvates, hydrates and pharmaceutically acceptable salts.

[0084] The term "stereoisomer" includes R or S isomers (or D / L isomers) generated from centers containing asymmetric carbon or heteroatoms (e.g., P, S, Si, N), mirror-image or diastereoisomers generated from centers containing two or more chiral centers, geometric isomers such as trans and cis, etc.

[0085] The term "hydrate" refers to a compound of the present disclosure or a salt thereof, containing a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces. Hydrates of Formula I compounds may include stoichiometric or non-stoichiometric amounts of water bound by non-covalent intermolecular forces. Hydrates may contain one or more equivalents, preferably 1-5 equivalents, of water. These hydrates can be prepared by crystallizing a Formula I compound, its isomers, or pharmaceutically acceptable salts from water or an aqueous solvent.

[0086] The term "solvent" refers to a compound or salt thereof disclosed herein, which contains a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. Preferred solvents include those that are volatile, non-toxic, and / or suitable for human administration.

[0087] The term "pharmaceutically acceptable salt" refers to a salt formed by the ionic interaction between a compound containing a carboxylic acid or amine functional group and a counterion, wherein the resulting salt is suitable for pharmaceutical use.

[0088] The compounds of Formula I according to this disclosure can be used in the form of pharmaceutically acceptable salts. Acid addition salts formed from pharmaceutically acceptable free acids are useful. Acid addition salts can be derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, and hypophosphoric acid; non-toxic organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanes, hydroxyalkanes, alkanedioic acids, aromatic acids, and aliphatic or aromatic sulfonic acids; or organic acids such as trifluoroacetic acid; or can be acetates, benzoates, citrates, lactates, maleates, gluconates, methanesulfonates, 4-toluenesulfonates, tartrates, fumarates, etc. Pharmaceutically non-toxic salts can include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, fluorides, acetates, propionates, decanoates, octanoates, acrylates, formates, isobutyrates, decanoates, heptanoates, propargylates, oxalates, malonates, succinates, octanoates, sebacic acid, fumarates, maleates, and buten-1,4-dicarboxylic acid. Salts, hexane-1,6-diacidates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, terephthalates, benzenesulfonates, toluenesulfonates, chlorobenzenesulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, β-hydroxybutyrates, glycolates, maleates, tartrates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, mandelates, etc.

[0089] The acid addition salts of this disclosure can be prepared by conventional methods. For example, the derivative of Formula I can be dissolved in an organic solvent such as methanol, ethanol, acetone, dichloromethane, or acetonitrile, followed by the addition of an organic or inorganic acid to form a precipitate, which is then filtered and dried. Alternatively, the crystalline derivative can be prepared in an organic solvent by vacuum distilling the solvent and excess acid, followed by drying the residue.

[0090] In addition, alkalis can be used to prepare pharmaceutically acceptable metal salts. For example, alkali metal or alkaline earth metal salts can be obtained by dissolving the compound in a solution containing an excess of alkali metal hydroxide or alkaline earth metal hydroxide, filtering out the insoluble salt of the compound, evaporating, and drying the filtrate. Pharmaceutically suitable metal salts include sodium, potassium, and calcium salts. The corresponding salts can also be obtained by reacting the alkali metal or alkaline earth metal salt with a suitable anionic salt such as silver nitrate.

[0091] The embodiments of the compound of formula I in this disclosure are not particularly limited, but may be specifically selected from the following examples, provided that the compound of formula I is not... .

[0092] In a first embodiment, this disclosure provides compounds of formula IA, IB, IC, ID, IE, IF, IG, IH or IJ, wherein dashed lines indicate single bonds or the absence of bonds;

[0093] Y represents H and C. 1-6 Alkyl, -C (= O) (R 1 ) or -P (= O) (R 2 ) (R 3 );

[0094] R 1 To R 3 Each independently is C 1-6 Alkyl or phenyl;

[0095] X is H or C 1-6 alkyl;

[0096] R is -C n Alkylene-LMR 4 ;

[0097] n is an integer from 0 to 10, and -C n Alkyl groups may optionally contain carbon-carbon double bonds;

[0098] L is C (= O) or CH2;

[0099] M represents O, S, N (R) 5 (or does not exist;)

[0100] R 4 Selected from H, unsubstituted or one or more halogen-substituted C1-6 Alkyl, unsubstituted 3-10 membered cycloalkyl or one or more halogen-substituted 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered heterocycloalkyl, -C (= O)(R 6 ) and -S(= O)2(R 7 );

[0101] R 5 For H or C 1-6 alkyl;

[0102] R 6 and R 7 Each independently is C 1-6 alkyl;

[0103] V is H or C 1-6 alkyl.

[0104] In other embodiments of the first embodiment, the compound may be the first embodiment in which L is C (= O) or CH2.

[0105] In other embodiments of the first embodiment, the compound may be wherein Y is -C (= O)(R 1 ) or -P(= O)(R 2 (R) 3 -C (= O) (R) 1 -P (= O) (R) 2 (R) 3 ); H; or C 1-6 The first embodiment of the alkyl group.

[0106] In other embodiments of the first implementation scheme, n can be selected from integers in the range of 0 to 9, 0 to 8, 0 to 7, 0 to 6, 0 to 5, 0 to 4, and 0 to 3.

[0107] In other embodiments of the first implementation scheme, C 1-6 Alkyl groups can be C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl, C 1-2 Alkyl or methyl substitution.

[0108] In other embodiments of the first embodiment, the compound may be wherein M is O, S, N (R 5 ), or does not exist; O, S, or N (R 5 ); O; or N (R) 5 The first implementation plan of ).

[0109] In other embodiments of the first embodiment, the heteroaryl or heterocyclic alkyl group may contain one or more heteroatoms selected from O, N, and S; O and N; or N. The number of heteroatoms contained in the heteroaryl or heterocyclic alkyl group may be 1 to 3, or 1 to 2.

[0110] In a second embodiment, this disclosure provides compounds of formula IA or IE, wherein dashed lines indicate single bonds or the absence of bonds;

[0111] Y represents H and C. 1-6 Alkyl, -C (= O) (R 1 ) or -P (= O) (R 2 ) (R 3 );

[0112] R 1 To R 3 Each independently is C 1-6 Alkyl or phenyl;

[0113] X is H or C 1-6 alkyl;

[0114] R is -C n Alkylene-LMR 4 ;

[0115] n is an integer from 0 to 10, and -C n Alkyl groups may optionally contain carbon-carbon double bonds;

[0116] L is C (= O) or CH2;

[0117] M represents O, S, N (R) 5 (or does not exist;)

[0118] R 4 Selected from H, unsubstituted or one or more halogen-substituted C 1-6 Alkyl, unsubstituted 3-10 membered cycloalkyl or one or more halogen-substituted 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered heterocycloalkyl, -C (= O)(R 6 ) and -S(= O)2(R 7 );

[0119] R 5 For H or C 1-6 alkyl;

[0120] R 6 and R 7 Each independently is C 1-6 alkyl.

[0121] In other embodiments of the second embodiment, the compound may be a second embodiment in which L is C (= O) or CH2.

[0122] In other embodiments of the second embodiment, the compound may be wherein Y is -C (= O)(R 1 ) or -P(= O)(R 2 (R) 3 -C (= O) (R) 1 -P (= O)(R) 2 (R) 3 ); H; or C 1-6 A second embodiment of the alkyl group.

[0123] In other embodiments of the second implementation scheme, n can be selected from integers in the range of 0 to 9, 0 to 8, 0 to 7, 0 to 6, 0 to 5, 0 to 4, and 0 to 3.

[0124] In other embodiments of the second implementation scheme, C 1-6 Alkyl groups can be C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl, C 1-2 Alkyl or methyl substitution.

[0125] In other embodiments of the second embodiment, the compound may be wherein M is O, S, N(R) 5 ) or does not exist; O, S or N (R 5 ); O; or N(R) 5 The second implementation plan.

[0126] In other embodiments of the second embodiment, the heteroaryl or heterocyclic alkyl group may contain heteroatoms selected from O, N, and S; O and N; or N. The number of heteroatoms contained in the heteroaryl or heterocyclic alkyl group may be 1 to 3, or 1 to 2.

[0127] In other embodiments of the second implementation scheme, dashed lines represent single bonds or bonds that do not exist;

[0128] Y is -C (= O) (R) 1 );

[0129] R 1 C 1-6 alkyl;

[0130] X is H or C 1-6 alkyl;

[0131] R is -C n Alkylene-LMR 4 ;

[0132] n is an integer between 0 and 10;

[0133] L is CH2;

[0134] M is O, S, N(R) 5 (or does not exist;)

[0135] R 4 C is either unsubstituted or substituted with one or more halogens. 1-6 Alkyl, unsubstituted 3- to 10-membered cycloalkyl, or 6- to 10-membered aryl, 5- to 10-membered heteroaryl, -C (= O)(R 6 ) or -S (= O)2(R 7 );

[0136] R 5 For H or C 1-6 alkyl;

[0137] R 6 and R 7 Each independently is C 1-6 alkyl.

[0138] In other embodiments of the second implementation scheme, dashed lines represent single bonds or bonds that do not exist;

[0139] Y is -C (= O) (R) 1 );

[0140] R 1 C 1-6 alkyl;

[0141] X is H or C 1-6 alkyl;

[0142] R is -C n Alkylene-LMR 4 ;

[0143] n is an integer between 0 and 10;

[0144] L is CH2;

[0145] M is O;

[0146] R 4 C is either unsubstituted or substituted with one or more halogens. 1-6 Alkyl, unsubstituted 3- to 10-membered cycloalkyl, or 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocycloalkyl, -C (= O)(R 6 ), or -S (= O)2(R 7 );as well as

[0147] R6 and R 7 Each independently is C 1-6 alkyl.

[0148] In the third embodiment, this disclosure provides compounds of formula IA, IB, IC, ID, IE, IF, IG, IH or IJ, wherein dashed lines indicate single bonds or the absence of bonds;

[0149] Y represents H and C. 1-6 Alkyl, -C (= O) (R 1 ) or -P (= O) (R 2 (R) 3 );

[0150] R 1 To R 3 Each independently is C 1-6 Alkyl or phenyl;

[0151] X is H or C 1-6 alkyl;

[0152] R is -C n Alkylene-LMR 4 ;

[0153] n is an integer from 0 to 10, and -C n Alkyl groups may optionally contain carbon-carbon double bonds;

[0154] L is C (= O);

[0155] M represents O, S, N (R) 5 (or does not exist;)

[0156] R 4 Selected from H, unsubstituted or one or more halogen-substituted C 1-6 Alkyl, unsubstituted 3-10 membered cycloalkyl or one or more halogen-substituted 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered heterocycloalkyl, -C (= O)(R 6 ) and -S(= O)2(R 7 );

[0157] R 5 For H or C 1-6 alkyl;

[0158] R 6 and R 7 Each independently is C 1-6 alkyl;

[0159] V is H or C 1-6 alkyl.

[0160] In other embodiments of the third embodiment, the compound may be wherein Y is -C (= O)(R 1 ) or -P(= O) (R 2 (R) 3 -C (= O) (R) 1 -P (= O) (R) 2 (R) 3 ); H; or C 1-6 A third embodiment of the alkyl group.

[0161] In other implementations of the third implementation scheme, n can be selected from integers in the range of 0 to 9, 0 to 8, 0 to 7, 0 to 6, 0 to 5, 0 to 4, and 0 to 3.

[0162] In other embodiments of the third implementation scheme, C 1-6 Alkyl groups can be C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl, C 1-2 Alkyl or methyl substitution.

[0163] In other embodiments of the third embodiment, the compound may be wherein M is O, S, or N (R 5 ); O; or N(R) 5 The third implementation plan.

[0164] In other embodiments of the third embodiment, the heteroaryl or heterocyclic alkyl group may contain heteroatoms selected from O, N, and S; O and N; or N. The number of heteroatoms contained in the heteroaryl or heterocyclic alkyl group may be 1 to 3, or 1 to 2.

[0165] In a fourth embodiment, the present invention provides compounds of formula IA, IB, IC, ID, IE, IF, IG, IH, or IJ, wherein Y is H or C. 1-6 Alkyl, -C (= O) (R 1 ) or -P (= O) (R 2 (R) 3 );

[0166] R 1 To R 3 Each independently is C 1-6 Alkyl or phenyl;

[0167] X is H or C 1-6 alkyl;

[0168] R is -C n Alkylene-LMR 4 ;

[0169] n is an integer from 0 to 10, and -C n Alkyl groups may optionally contain carbon-carbon double bonds;

[0170] L is C (= O) or CH2;

[0171] M represents O, S, N (R) 5 (or does not exist;)

[0172] R 4 C is either unsubstituted or substituted with one or more halogens. 1-6 Alkyl, unsubstituted 3- to 10-membered cycloalkyl, or 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocycloalkyl, -C (= O)(R 6 ), or -S (= O)2(R 7 );

[0173] R 5 For H or C 1-6 alkyl;

[0174] R 6 and R 7 Each independently is C 1-6 alkyl;

[0175] V is H or C 1-6 alkyl.

[0176] In other embodiments of the fourth embodiment, the compound may be wherein Y is -C (= O)(R 1 ) or -P (= O)(R 2 (R) 3 -C (= O)(R) 1 -P (= O)(R) 2 (R) 3 ); H; or C 1-6 A fourth embodiment of the alkyl group.

[0177] In other implementations of the fourth implementation scheme, n can be selected from integers in the range of 0 to 9, 0 to 8, 0 to 7, 0 to 6, 0 to 5, 0 to 4, and 0 to 3.

[0178] In other embodiments of the fourth implementation scheme, C 1-6 Alkyl groups can be C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl, C 1-2 Alkyl or methyl substitution.

[0179] In other embodiments of the fourth embodiment, the compound may be a fourth embodiment in which L is C (= O); or CH2.

[0180] In other embodiments of the fourth embodiment, the compound may be wherein M is O, S, or N(R) 5 ); O; or N(R) 5 The fourth implementation plan.

[0181] In other embodiments of the fourth embodiment, the heteroaryl or heterocyclic alkyl group may contain heteroatoms selected from O, N, and S; O and N; or N. The number of heteroatoms contained in the heteroaryl or heterocyclic alkyl group may be 1 to 3, or 1 to 2.

[0182] In a fifth embodiment, the present invention provides compounds of formula IA or IE, wherein Y is -C (= O)(R 1 ) or -P(= O)(R 2 (R) 3 );

[0183] R 1 To R 3 Each independently is C 1-6 alkyl;

[0184] X is H or C 1-6 alkyl;

[0185] R is -C n Alkylene-LMR 4 ;

[0186] n is an integer between 0 and 10;

[0187] L is C (= O) or CH2;

[0188] M represents O, S, N (R) 5 (or does not exist;)

[0189] R 4 C is either unsubstituted or substituted with one or more halogens. 1-6 Alkyl, unsubstituted 3- to 10-membered cycloalkyl, or 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocycloalkyl, -C (= O)(R 6 ), or -S (= O)2(R 7 );

[0190] R 5 For H or C 1-6 alkyl;

[0191] R 6 and R 7 Each independently is C 1-6 alkyl.

[0192] In other embodiments of the fifth implementation scheme, n can be selected from integers in the range of 0 to 9, 0 to 8, 0 to 7, 0 to 6, 0 to 5, 0 to 4, and 0 to 3.

[0193] In other embodiments of the fifth implementation plan, C 1-6 Alkyl groups can be C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl, C 1-2 Alkyl or methyl substitution.

[0194] In other embodiments of the fifth implementation scheme, L can be C (= O); or CH2.

[0195] In other embodiments of the fifth embodiment, the compound may be wherein M is O, S, N(R) 5 ); O; or N(R) 5 The fifth implementation plan.

[0196] In other embodiments of the fifth embodiment, the heteroaryl or heterocyclic alkyl group may contain heteroatoms selected from O, N, and S; O and N; or N. The number of heteroatoms contained in the heteroaryl or heterocyclic alkyl group may be 1 to 3, or 1 to 2.

[0197] In a sixth embodiment, the present invention provides a compound of formula IA, wherein Y is -C (= O)(R 1 ) or -P (= O)(R 2 (R) 3 );

[0198] R 1 To R 3 Each independently is C 1-6 alkyl;

[0199] X is H or C 1-6 alkyl;

[0200] R is -C n Alkylene-LMR 4 ;

[0201] n is an integer between 0 and 10;

[0202] L is C (= O) or CH2;

[0203] M is O or N (R) 5 );

[0204] R 4 C is either unsubstituted or substituted with one or more halogens. 1-6Alkyl, unsubstituted 3- to 10-membered cycloalkyl, or 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocycloalkyl, -C (= O)(R 6 ), or -S (= O)2(R 7 );

[0205] R 5 For H or C 1-6 alkyl;

[0206] R 6 and R 7 Each independently is C 1-6 alkyl.

[0207] In other implementations of the sixth implementation scheme, n can be selected from integers in the range of 0 to 9, 0 to 8, 0 to 7, 0 to 6, 0 to 5, 0 to 4, and 0 to 3.

[0208] In other embodiments of the sixth implementation scheme, L can be C (= O); or CH2.

[0209] In other embodiments of the sixth implementation scheme, when L is C (= O), M can be N(R) 5 ); or when L is CH2, M can be O.

[0210] In other implementation schemes of the sixth implementation scheme, C 1-6 Alkyl groups can be C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl, C 1-2 Alkyl or methyl substitution.

[0211] In other embodiments of the sixth implementation scheme, M is O, S, or N(R) 5 ); O; or N(R) 5 In other embodiments of the sixth embodiment, the heteroaryl or heterocyclic alkyl group may contain heteroatoms selected from O, N, and S; O and N; or N. The number of heteroatoms contained in the heteroaryl or heterocyclic alkyl group may be 1 to 3, or 1 to 2.

[0212] In a seventh embodiment, the present invention provides a compound of formula IA, wherein Y is -C (= O)(R 1 ) or -P (= O)(R 2 ) (R 3 );

[0213] R 1 To R 3 Each independently is C 1-6 alkyl;

[0214] X is H or C1-6 alkyl;

[0215] R is -C n Alkylene-LMR 4 ;

[0216] n is an integer between 0 and 10;

[0217] L is CH2;

[0218] M is O;

[0219] R 4 C is either unsubstituted or substituted with one or more halogens. 1-6 Alkyl, unsubstituted 3- to 10-membered cycloalkyl, or 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocycloalkyl, -C (= O)(R 6 ), or -S (= O)2(R 7 );

[0220] R 5 For H or C 1-6 alkyl;

[0221] R 6 and R 7 Each independently is C 1-6 alkyl.

[0222] In other embodiments of the seventh implementation scheme, n can be selected from integers in the range of 0 to 9, 0 to 8, 0 to 7, 0 to 6, 0 to 5, 0 to 4, and 0 to 3.

[0223] In other embodiments of the seventh implementation scheme, C 1-6 Alkyl groups can be C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl, C 1-2 Alkyl or methyl substitution.

[0224] In other embodiments of the seventh embodiment, the compound may be wherein M may be O, S, or N (R 5 ); O; or N (R) 5 The fifth implementation plan.

[0225] In other embodiments of the seventh embodiment, the heteroaryl or heterocyclic alkyl group may contain heteroatoms selected from O, N, and S; O and N; or N. The number of heteroatoms contained in the heteroaryl or heterocyclic alkyl group may be 1 to 3, or 1 to 2.

[0226] In other embodiments of the seventh implementation scheme, dashed lines represent single bonds or bonds that do not exist;

[0227] Y is -C (= O) (R) 1 );

[0228] R 1 C 1-6 alkyl;

[0229] X is C 1-6 alkyl;

[0230] R is -C n Alkylene-LMR 4 ;

[0231] n is an integer between 0 and 10;

[0232] L is CH2;

[0233] M is O;

[0234] R 4 C 1-6 alkyl.

[0235] In other embodiments of the seventh implementation scheme, dashed lines represent single bonds or bonds that do not exist;

[0236] Y is -C (= O) (R) 1 );

[0237] R 1 C 1-6 alkyl;

[0238] X is C 1-6 alkyl;

[0239] R is -C n Alkylene-LMR 4 ;

[0240] n is an integer between 0 and 5;

[0241] L is CH2;

[0242] M is O;

[0243] R 4 C 1-6 alkyl.

[0244] In the eighth embodiment, this disclosure provides a compound of formula IA, wherein Y is H;

[0245] R 1 To R 3 Each independently is C 1-6 alkyl;

[0246] X is H or C 1-6 alkyl;

[0247] R is -Cn Alkylene-LMR 4 ;

[0248] n is an integer between 0 and 10;

[0249] L is C (= O);

[0250] M is O;

[0251] R 4 For H.

[0252] In a ninth embodiment, the present invention provides a compound of formula IA, wherein the dashed line indicates a single bond or the absence of a bond;

[0253] Y is -P (= O)(R) 2 (R) 3 );

[0254] R 1 To R 3 Each independently is C 1-6 Alkyl or phenyl;

[0255] X is C 1-6 alkyl;

[0256] R is -C n Alkylene-LMR 4 ;

[0257] n is an integer between 0 and 10;

[0258] L is C (= O);

[0259] M is O;

[0260] R 4 C 1-6 alkyl.

[0261] In other embodiments of the ninth implementation scheme, dashed lines represent single bonds or bonds that do not exist;

[0262] Y is -P (= O)(R) 2 (R) 3 );

[0263] R 1 To R 3 Each independently is C 1-6 alkyl;

[0264] X is C 1-6 alkyl;

[0265] R is -C n Alkylene-LMR 4 ;

[0266] n is an integer between 0 and 5;

[0267] L is C (= O);

[0268] M is O;

[0269] R 4 C 1-6 alkyl.

[0270] Compounds of Formula I may be selected from compounds having the following structures.

[0271] Table 1.

[0272]

[0273]

[0274]

[0275]

[0276]

[0277]

[0278]

[0279]

[0280] The compounds disclosed herein (including their stereoisomers, hydrates, solvates, and pharmaceutically acceptable salts) can be administered in a variety of oral and parenteral dosage forms for clinical use. When formulated, dosage forms are typically prepared using conventional diluents or excipients such as fillers, swelling agents, binders, wetting agents, disintegrants, and surfactants. Solid dosage forms for oral administration include tablets, pills, powders, granules, and capsules. These solid dosage forms can be prepared by mixing one or more compounds with at least one excipient such as starch, calcium carbonate, sucrose, lactose, or gelatin. In addition to basic excipients, lubricants such as magnesium stearate and talc may also be used. Liquid dosage forms for oral administration include suspensions, internal solutions, emulsions, and syrups. These may contain simple diluents such as water or liquid paraffin and may further include excipients such as wetting agents, sweeteners, flavoring agents, and preservatives. Parenteral dosage forms may include sterile aqueous solutions, non-aqueous solvents, suspensions, and emulsions. Non-aqueous solvents and suspension media can be used, such as propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate.

[0281] Pharmaceutical compositions containing compounds of this disclosure (including their stereoisomers, hydrates, solvates, and pharmaceutically acceptable salts) as active ingredients may be administered via a parenteral route. Parenteral administration may be performed via subcutaneous injection, intravenous injection, intramuscular injection, or intrapleural injection.

[0282] To formulate parenteral dosage forms, compounds (including their stereoisomers, hydrates, solvates, and pharmaceutically acceptable salts) can be mixed with water and stabilizers or buffers to prepare solutions or suspensions, which can be formulated into unit dosage forms such as ampoules or vials. The compositions may be sterile and / or may contain additives such as preservatives, stabilizers, humectants, emulsifiers, salts for osmotic adjustment, buffers, and other therapeutically useful substances. Formulations can be prepared by conventional methods such as mixing, granulation, or coating. Orally administered formulations may include, for example, tablets, pills, soft or hard capsules, solutions, suspensions, emulsions, syrups, granules, elixirs, and lozenges. In addition to the active ingredient, these formulations may contain diluents such as lactose, glucose, sucrose, mannitol, sorbitol, cellulose, and / or glycine; and lubricants such as silica, talc, stearic acid, and their magnesium or calcium salts and / or polyethylene glycol. Tablets may also contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethyl cellulose, and / or polyvinylpyrrolidone. In some cases, they may also contain disintegrants such as starch, agar, alginate or its sodium salt, effervescent mixtures and / or absorption enhancers, colorants, flavorings, and sweeteners.

[0283] In this disclosure, compounds (including their stereoisomers, hydrates, solvates, and pharmaceutically acceptable salts) are administered in therapeutically effective amounts. The term "therapeutically effective amount" refers to the range of amounts that produce a preventive, ameliorative, or therapeutic effect. Therapeuticly effective amounts may vary depending on the severity of the condition and the formulation, and the frequency of administration may vary depending on the age, weight, and physical condition of the subject. In one embodiment of the invention, the compound of formula I may be included in the pharmaceutical composition at a dose of at least 0.001 mg / kg, preferably at least 0.1 mg / kg, 1 mg / kg, 10 mg / kg, 100 mg / kg, or 250 mg / kg, and may be included in an amount that does not produce toxicity. For example, the dose may be selected from a range of up to 10 g / kg or up to 1 g / kg. The upper limit of the amount of the compound (including its stereoisomers, hydrates, solvates, and pharmaceutically acceptable salts) contained in the pharmaceutical composition may be suitably selected by those skilled in the art.

[0284] On the other hand, the present invention provides a pharmaceutical composition comprising a compound of formula I (including its stereoisomers, solvates, hydrates or pharmaceutically acceptable salts) as an active ingredient.

[0285] The pharmaceutical composition may further include pharmaceutically acceptable additives.

[0286] On the other hand, the present invention provides a pharmaceutical composition for the prevention or treatment of vascular endothelial dysfunction or vascular leakage diseases, the composition containing a compound of formula I (including its stereoisomers, solvates, hydrates or pharmaceutically acceptable salts) as an active ingredient.

[0287] On the other hand, the present invention provides a health-promoting functional food composition for preventing or improving vascular endothelial dysfunction or vascular leakage diseases, the composition containing a compound of formula I (including its stereoisomers, solvates, hydrates or pharmaceutically acceptable salts) as an active ingredient.

[0288] On the other hand, the present invention provides a method for treating vascular endothelial dysfunction or vascular leakage diseases, the method comprising administering a compound of formula I (including its stereoisomers, solvates, hydrates or pharmaceutically acceptable salts) to a subject in need.

[0289] On the other hand, the present invention provides the use of a compound of formula I (including its stereoisomers, solvates, hydrates or pharmaceutically acceptable salts) in the preparation of a medicament for the prevention or treatment of vascular endothelial dysfunction or vascular leakage diseases.

[0290] As used in this article, examples of “vascular leakage disease” or “vascular endothelial dysfunction” include diabetes, inflammation, retinopathy, diabetic retinopathy, macular degeneration, glaucoma, stenosis, restenosis, arteriosclerosis, atherosclerosis, cerebral edema, arthritis, arthropathy, uveitis, inflammatory bowel disease, macular edema, cancer, hyperlipidemia, ischemic disease, diabetic foot ulcer, pulmonary hypertension, acute lung injury, myocardial ischemia, heart failure, acute limb ischemia, myocardial infarction, stroke, ischemia or reperfusion injury, vascular leakage syndrome (VLS), edema, transplant rejection, burns, acute or adult respiratory distress syndrome (ARDS), sepsis, or autoimmune diseases.

[0291] The following describes a method for preparing compounds of formula IA according to this disclosure.

[0292] Option A

[0293]

[0294] Compound IA can be prepared according to scheme A.

[0295] The compound of formula IA-1 was coupled with a glucal derivative to obtain the compound of formula IA.

[0296] In scheme A, the dashed circle, the dashed line, and X, Y, and R are defined as described above for equation I.

[0297] Coupling reactions with glucosene derivatives can be carried out under known conditions, typically in the presence of a catalyst and using an organic solvent.

[0298] The reaction catalyst can be selected from cationic perfluoro-1-alkyl sulfonates (where the cation is lithium, sodium, potassium or cesium, and the alkyl group is a straight-chain or branched perfluorinated C). 1-10 Alkyl groups, (S)-camphorsulfonic acid, iodine, Amberlyst 15, and boron trifluoride ether compounds, or mixtures thereof. However, the reaction catalyst is not limited to those mentioned above. In one embodiment of the invention, a mixture of lithium nonafluoro-1-butylsulfonate (Li-NFBS) and (S)-camphorsulfonic acid is used. This is merely an example and should not be construed as limiting.

[0299] This disclosure can be implemented according to the general procedure 4 described below.

[0300] The intermediate compound of Formula I-1 can be prepared from starting materials such as pregnanelonone or epipregnanelonone by known methods, such as the improved method disclosed in U.S. Patent 8,889,840B2.

[0301] Based on the Y substituent, the compound of formula I can be prepared stepwise according to the following scheme A-1.

[0302] Option A-1

[0303]

[0304] In scheme A-1, Ya is an acetyl group; Yc is a phosphorylated C group. 1-6 Alkyl ester; and Hal indicates halogen.

[0305] Compounds of formula IAa can be prepared from compounds of formula IB as shown in scheme A-1.

[0306] Compounds of formula IAb can be prepared from compounds of formula IAa via a deprotection reaction of the glucoseene substituent. This reaction can be carried out according to general method 3a or general method 3b, as described below.

[0307] The deprotection reaction in this step is a routine conversion of ester functional groups to alcohol functional groups, usually carried out in the presence of an acid catalyst. It can also be carried out under conditions different from those in general methods 3a or 3b.

[0308] Compounds of formula IAc can be prepared from compounds of formula IAb by phosphorylation-esterification reaction, which can be carried out in the presence of a base such as a tertiary amine using an organic solvent.

[0309] Compounds of formula IC can be used as starting materials for deprotection reactions in the preparation of compounds of formula IB.

[0310]

[0311] Compounds of formula IC can be obtained via the well-known Wittig reaction, as shown in the reaction route below. Depending on the type of R substituent, further substituent modifications can be made after the Wittig reaction.

[0312]

[0313] Compounds of formulas ID, IE, IF, IG, IH, and IJ can be prepared by coupling with glucose olefin derivatives using the same method as that used to prepare compounds of formula IA.

[0314] The following synthetic examples illustrate the preparation of compounds according to this disclosure.

[0315] These embodiments are for illustrative purposes only, and it will be apparent to those skilled in the art that other compounds falling within the scope of this disclosure can be prepared by making modifications within the obvious scope of these embodiments.

[0316] Example 1:

[0317] Example 1-1: Preparation of compound IA-1

[0318] Synthetic Example A1. 1-((3S,5R,8R,9S,10S,13S,14S,17S)-10,13-dimethyl-3-((tetramethyl-3-(tetrazolium chloride)) Preparation of 2H-pyran-2-yl)oxy)hexadecylhydro-1H-cyclopentan[a]phenanthrene-17-yl)ethyl-1-one

[0319]

[0320] At ambient temperature, pregnane (epipregnanolone) (530.0 mg, 3.14 mmol) was added to a mixture of dichloromethane (30 mL) and tetrahydrofuran (THF, 3 mL). 3,4-Dihydro-2H-pyran (303.6 μL, 3.33 mmol) was added to the reaction mixture. p-Toluenesulfonic acid monohydrate (15.8 mg, 0.08 mmol) was dissolved in THF (0.08 mL) and added dropwise to the mixture, which was stirred at ambient temperature for 1 hour. The reaction was quenched with water at ambient temperature, and the mixture was washed twice with dichloromethane and brine. The washed mixture was dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure. The residue was purified by silica gel column chromatography to give the desired compound A1 (275.0 mg, 41% yield).

[0321] 1H NMR(500 MHz, CDCl3) δ 4.65 - 4.62(m, 1H), 3.97 - 3.93(m, 1H), 3.93- 3.83(m, 1H), 3.51 - 3.42(m, 1H), 2.52(t, J = 8.9 Hz, 1H), 2.10(s, 4H), 2.03- 1.96(m, 1H), 1.93 - 1.82(m, 3H), 1.81 - 1.59(m, 5H), 1.59 - 1.48(m, 8H),1.47(d, J = 1.3 Hz, 2H), 1.46 - 1.26(m, 7H), 1.26 - 1.20(m, 1H), 1.20 - 1.15(m, 2H), 1.15 - 1.01(m, 1H), 0.93(d, J = 0.8 Hz, 3H), 0.59(s, 3H).

[0322] The following compounds were prepared using the same method as in Synthesis Example A1.

[0323]

[0324] Intermediate compound A26 was prepared as shown in Scheme 1-1 below.

[0325] Option 1-1

[0326]

[0327] Step 1:

[0328] Synthetic Example A3: (E)-5-((3S,8S,9S,10R,13S,14S,17R)-10,13-dimethyl-3-((tetramethyl-3- ... 2H-pyran-2-yl)oxy)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecano-1H-cyclopentanol[a] ]Phenylacetic acid (17-yl)hex-4-enoic acid

[0329] General Method 5

[0330] The reaction was carried out using starting materials prepared in the same manner as in Synthesis Example A1.

[0331] 3-Carboxypropyltriphenylphosphonium bromide (16.07 g, 37.44 mmol) was dissolved in toluene (374 mL), and potassium tert-pentanoxide (1.7 M in toluene, 44.1 mL, 74.89 mmol) was added at ambient temperature. The reaction mixture was stirred at 110 °C for 1 hour, and then cooled to 60 °C. 1-((3S,8S,9S,10R,13S,14S,17S)-10,13-dimethyl-3-((tetrahydro-2H-pyran-2-yl)oxy)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecanohydro-1H-cyclopentan[a]phenanthrene-17-yl)ethyl-1-one (5.0 g, 12.48 mmol) was added dropwise, and the reaction mixture was reheated to 110 °C and stirred for 16 hours. After the reaction was complete, the mixture was cooled to 40°C and washed successively with saturated ammonium chloride aqueous solution, ethyl acetate, water, and brine. The washed mixture was dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure. The residue was purified by silica gel column chromatography to give the target compound A3 (2.54 g, 43%).

[0332] Synthetic Examples A4, A5, A41, A48, A53, A64, A77 and A81 were prepared according to General Method 5.

[0333]

[0334] Step 2:

[0335] Synthetic Example A7. (E)-5-((3S,8S,9S,10R,13S,14S,17R)-10,13-dimethyl-3- ((tetrahydro-2H-pyran-2-yl)oxy)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecano-1H-cyclopentane [a]phenanthrene-17-yl)hex-4-enoate methyl ester

[0336] Synthetic Example A3 (101 mg, 0.22 mmol) was dissolved in a mixture of methanol and dichloromethane (1:2, 1.5 mL). Trimethylsilyldiazomethane (2M Et2O solution, 0.70 mL, 0.43 mmol) was slowly added dropwise at 0 °C. The reaction mixture was stirred at room temperature for 3 hours, then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the desired compound A7 (40.7 mg, 39% yield).

[0337] 1H NMR(500 MHz, CDCl3) δ 5.39 - 5.31(m, 1H), 5.16 - 5.13(m, 1H), 4.72- 4.71(m, 1H), 3.97 - 3.87(m, 1H), 3.66(s, 3H), 3.58 - 3.43(m, 2H), 2.40 -2.30(m, 6H), 2.25 - 2.15(m, 1H), 2.06 - 1.94(m, 2H), 1.94 - 1.49(m, 19H),1.49 - 1.37(m, 3H), 1.23 - 1.12(m, 2H), 1.10 - 1.02(m, 2H), 1.01(s, 3H), 0.97- 0.92(m, 1H), 0.52(s, 3H).

[0338] The following compounds were prepared using the same method as described above.

[0339]

[0340] Step 3:

[0341] Synthetic Example A26. (E)-5-((3S,8S,9S,10R,13S,14S,17R)-3-hydroxy-10,13-dimethyl 2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecanoic acid-1H-cyclopentan[a]phenanthrene-17-yl)hex-4-enoic acid Methyl ester

[0342]

[0343] General Step 3 b

[0344] Synthetic Example A7 was dissolved in methanol (5 mL), and p-toluenesulfonic acid monohydrate (70.0 mg, 0.14 mmol) was added at ambient temperature. The reaction mixture was refluxed with stirring for 5 hours. The solvent was removed by vacuum distillation. The residue was extracted with ethyl acetate and saturated aqueous sodium bicarbonate solution, and the resulting organic layer was washed with brine. The organic layer was then dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure. The residue was purified by silica gel column chromatography to give the desired compound A26 (34.0 mg, 59% yield).

[0345] 1H NMR(500 MHz, CDCl3) δ 5.36 - 5.34(m, 1H), 5.18 - 5.12(m, 1H), 3.67(s, 3H), 3.57 - 3.48(m, 1H), 2.36(d, J = 3.2 Hz, 4H), 2.33 - 2.19(m, 2H),2.04 - 1.95(m, 2H), 1.89 - 1.74(m, 4H), 1.71 - 1.37(m, 12H), 1.20 - 1.14(m,2H), 1.12 - 1.03(m, 2H), 1.01(s, 3H), 0.98 - 0.93(m, 1H), 0.53 (s, 3H).

[0346] The following compounds were prepared using the same method as described above.

[0347]

[0348] Examples 1-2:

[0349] Option 1-2:

[0350]

[0351] Step 1:

[0352] Synthetic Example A10: 2- (((3S,8S,9S,10R,13S,14S,17R)-17- ((E)-5-methoxypentyl- 2-En-2-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecano-1H-cyclopentane [a]phenanthrene-3-yl)oxy)tetrahydro-2H-pyran

[0353] This synthetic example A10 was prepared according to general method 5.

[0354] 1 H NMR(500 MHz, CDCl3) δ 5.35(dd, J1= 8.1 Hz, J2= 5.6 Hz, 1H), 5.20 -5.15(m, 1H), 4.71(d, J = 4.6 Hz, 1H), 3.92(td, J1= 7.1 Hz, J2= 3.4 Hz, 1H),3.58 - 3.45(m, 2H), 3.38 - 3.34(m, 5H), 2.37-2.31(m, 3H), 2.06 - 1.95(m, 2H),1.93 - 1.76(m, 5H), 1.75 - 1.40(m, 16H), 1.23 - 1.03(m, 4H), 1.01(s, 3H),0.94(dt, J1= 11.7 Hz, J2= 5.9 Hz, 1H), 0.54(s, 3H). C30 H 49 O3 + MS(m / z) [M+H] + The calculated value is 457.36, and the measured value is 457.4.

[0355] Synthetic Examples A21, A57 to A59. These synthetic examples were prepared by the same method as described above.

[0356] Step 2:

[0357] Synthesis Example A30 (3S, 8S, 9S, 10R, 13S, 14S, 17R)-17- ((E)-5-methoxypent-2-ene- 2-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecano-1H-cyclopentane[a] phenanthrene-3-ol

[0358] General Method 3a

[0359] Synthetic Example A10 was dissolved in acetonitrile (0.15 mL) and tetrahydrofuran (0.15 mL). 6N hydrochloric acid aqueous solution (0.28 mL) was added to this solution at 0 °C, and the mixture was stirred for 2 hours. The reaction was brought to completion with saturated sodium bicarbonate aqueous solution, and the mixture was extracted twice with ethyl acetate. The resulting organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure. The residue was purified by silica gel column chromatography to give the desired compound A30 (95.0 mg, 91% yield).

[0360] 1 H NMR(500 MHz, CDCl3) δ 5.36(dd, J1 = 5.0 Hz, J2 = 2.4 Hz, 1H), 5.21- 5.15(m, 1H), 3.55 - 3.50(m, 1H), 3.39 - 3.34(m, 5H), 2.36 - 2.19(m, 4H),2.08 - 1.94(m, 2H), 1.89 - 1.76(m, 4H), 1.69 - 1.41(m, 11H), 1.22 - 1.03(m,4H), 1.01(s, 3H), 0.96(td, J1 = 11.7 Hz, J2 = 4.8 Hz, 1H), 0.54(s, 3H). For C 25 H 41 O2 + MS(m / z) [M+H] + The calculated value is 373.30, and the measured value is 373.4.

[0361] Synthetic Examples A34, A60 to A62. These synthetic examples were prepared by the same method as described above.

[0362] Examples 1-3:

[0363] Synthetic Examples 1-3 were prepared according to the following schemes 1-3.

[0364] Option 1-3

[0365]

[0366] Step 1:

[0367] Synthesis Example 1-1:

[0368] General Method 1

[0369] The compound from Synthetic Example A8 (50.0 g, 100.3 mmol) was dissolved in tetrahydrofuran (150 mL), and lithium aluminum hydride (LAH, 5.7 g, 150.5 mmol) was added dropwise at 0 °C. The reaction mixture was then stirred at 0 °C for 2 hours. The reaction was completed with water, and the mixture was filtered through diatomaceous earth. The filtrate was extracted twice with ethyl acetate, and the resulting organic layer was washed twice with brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure. The residue was purified by silica gel column chromatography to give the desired compound 1-1 (44.2 g, 39% yield).

[0370] 1 H NMR(500 MHz, CDCl3) δ 5.35 - 5.32(m, 1H), 5.17 - 5.14(m, 1H), 4.71- 4.69(m, 1H), 3.93 - 3.88(m, 1H), 3.65 - 3.62(m, 2H), 3.55 - 3.45(m, 2H), 2.60 - 2.34(m, 1H), 2.07 - 1.96(m, 4H), 1.86 - 1.37(m, 25H), 1.26 - 0.93(m,9H), 0.52(s, 3H).

[0371] Synthetic Examples A11-A14, A44, A50, A65, and A78. These synthetic examples are based on Synthetic Example 1-1. Prepared.

[0372] Table 2.

[0373]

[0374] Step 2:

[0375] Synthesis Examples 1-2:

[0376] General Method 2

[0377] The product of Synthesis Example 1-1 (24.2 g, 51.41 mmol) was dissolved in tetrahydrofuran (520 mL), and sodium hydride (NaH, 4.11 g, 102.81 mmol) was added dropwise at 0 °C. The reaction mixture was then stirred for 20 min. Methyl iodine (MeI, 4.8 mL, 77.11 mmol) was slowly added to the reaction mixture, and the mixture was stirred at 40 °C. After 3 hours, an equal volume of MeI was added dropwise, and the mixture was stirred for another 3 hours. The reaction was completed with water, and the reaction mixture was extracted with ethyl acetate. The resulting reaction mixture was washed with water and brine, and the resulting organic layer was dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure. The residue was purified by silica gel column chromatography to give the desired compounds 1-2 (18.5 g, 39% yield).

[0378] 1 H NMR(500 MHz, CDCl3) δ 5.35 - 5.32(m, 1H), 5.15(t, J = 7.5 Hz, 1H), 4.71 - 4.69(m, 1H), 3.93 - 3.89(m, 1H), 3.54 - 3.45(m, 2H), 3.36(t, J = 5.0Hz, 2H), 3.32(s, 3H), 2.35 - 2.34(m, 1H), 2.06 - 1.94(m, 4H), 1.88 - 1.35(m,25H), 1.19 - 1.00(m, 4H), 0.99(s, 3H), 0.93(dt, J1 = 12.5 Hz, J2= 5.0 Hz, 1H), 0.52 (s, 3H).

[0379] Under the conditions of general method 2 in synthetic examples 1-2, the following compounds A14-A20, A22-A24, A45, A51 and A66 were prepared using reactants corresponding to the substituents that substituted MeI.

[0380] Table 3.

[0381]

[0382] Step 3:

[0383] Synthesis Examples 1-3:

[0384]

[0385] Synthetic Examples 1-3 were prepared according to General Method 3a.

[0386] The compounds from Synthetic Examples 1-2 (4.0 g, 8.25 mmol) were dissolved in acetonitrile (10 mL) and tetrahydrofuran (10 mL). 6N hydrochloric acid (8.25 mL) was added to the reaction mixture at 0 °C, and the mixture was stirred for 3.5 h. The reaction was brought to completion with saturated sodium bicarbonate solution, and the mixture was extracted twice with ethyl acetate. The resulting organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure. The residue was purified by silica gel column chromatography to give the desired compounds 1-3 (1.22 g, 37% yield).

[0387] 1 H NMR(500 MHz, CDCl3) δ 5.35 - 5.33(m, 1H), 5.18 - 5.15(m, 1H), 3.55- 3.48(m, 1H), 3.36(t, J = 7.5 Hz, 2H), 3.32(s, 3H), 2.28 - 2.22(m, 4H), 2.06- 1.96(m, 4H), 1.85 - 1.77(m, 4H), 1.62 - 1.37(m, 15H), 1.19 - 1.04(m, 4H),1.00(s, 3H), 0.97 - 0.93(m, 1H), 0.53(s, 3H).

[0388] The following compounds were prepared according to general method 3a.

[0389] Table 4.

[0390]

[0391] Synthetic Examples A25 and A28: These synthetic examples were prepared according to general method 3b.

[0392]

[0393] Examples 1-4:

[0394] Option 1-4

[0395]

[0396] The intermediates of the synthetic examples 1-5 were prepared using general method 5 and general method 3b, as shown in reaction schemes 1-4.

[0397] Examples 1-5:

[0398] Option 1-5

[0399]

[0400] Synthetic Example A6: (E)-3- ((3S,8S,9S,10R,13S,14S,17R)-10,13-dimethyl-3- ((tetrahydro-2H-pyran-2-yl)oxy)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecano-1H-cyclopentane [a]-Phenylacetyl-17-yl)but-2-enoate methyl ester

[0401] In a dry, sealed tube, trimethyl phosphonoacetate (1.0 mL, 7.5 mmol) was dissolved in anhydrous tetrahydrofuran (THF, 8 mL). Under nitrogen atmosphere and at -78 °C, n-butyllithium (2.0 M, in cyclohexane, 3.7 mL, 7.5 mmol) was added dropwise, and the reaction mixture was stirred for 30 minutes. 1-((3S,8S,9S,10R,13S,14S,17S)-10,13-dimethyl-3-((tetrahydro-2H-pyran-2-yl)oxy)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecano-1H-cyclopentan[a]phenanthrene-17-yl)ethyl-1-one (1.0 g, 2.5 mmol) was dissolved in anhydrous tetrahydrofuran (4 mL) and added dropwise to the reaction mixture at -78 °C under nitrogen. The reaction mixture was then heated to 110 °C and stirred for 16 hours. After cooling to room temperature, the reaction mixture was washed successively with 1N hydrochloric acid aqueous solution, ethyl acetate, water, and brine. The washed mixture was then dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure. The residue was purified by silica gel column chromatography to give the desired compound A6 (275 mg, 24% yield).

[0402] 1 H NMR(500 MHz, CDCl3) δ 5.70(s, 1H), 5.38 - 5.32(m, 1H), 4.72(dd, J1= 5.0 Hz, J2 = 2.7 Hz, 1H), 3.95 - 3.85(m, 2H), 3.69(d, J = 2.2 Hz, 3H), 3.57- 3.44(m, 3H), 2.38 - 2.32(m, 2H), 2.17(dd, J1 = 10.0 Hz, J2 =1.2 Hz, 5H), 2.04 - 1.95(m, 1H), 1.92 - 1.65(m, 11H), 1.65 - 1.39(m, 15H), 1.31 - 0.93 (m, 10H), 0.59 (s, 3H).

[0403] Synthetic Example A27: (E)-3-((3S,8S,9S,10R,13S,14S,17R)-3-hydroxy-10,13-dimethyl 2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecanoic acid-1H-cyclopentan[a]phenanthrene-17-yl)but-2-enoic acid Methyl ester

[0404] Synthetic Examples 1-6 were prepared using this synthetic example A27 according to general method 3b.

[0405] Examples 1-6:

[0406] Option 1-6

[0407]

[0408] Synthesis Example A68: (3S, 8S, 9S, 10R, 13S, 14S, 17R)-17-((E)-7-methoxyhept-2-ene- 2-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecano-1H-cyclopentane[a] phenanthrene-3-methylmethanesulfonate

[0409] The compound from Synthetic Example 1-1 (1.0 g, 2.50 mmol) was dissolved in dichloromethane (12 mL), and triethylamine (TEA, 1.0 mL, 7.49 mmol) and methanesulfonyl chloride (MsCl, 0.40 mL, 4.99 mmol) were added at 0 °C. The reaction mixture was then stirred for 1 hour. The reaction was brought to completion with saturated sodium bicarbonate solution, and the mixture was extracted twice with ethyl acetate. The resulting organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure. The residue was purified by silica gel column chromatography to give the desired compound A68 (1.0 g, 84% yield). 1 H NMR(500 MHz, CDCl3) δ 5.41 (dt, J1 = 4.6Hz, J2 = 2.0 Hz, 1H), 5.19 - 5.14 (m, 1H), 4.51 (tt, J1 = 11.0 Hz, J2 = 5.1Hz, 1H), 3.36 (t, J = 6.6 Hz, 2H), 3.32 (s, 3H), 2.99 (s, 3H), 2.57 - 2.44(m, 2H), 2.08 - 1.96 (m, 5H), 1.90 (dt, J1 = 13.5 Hz, J2 = 3.7 Hz, 1H), 1.85 -1.74 (m, 3H), 1.70 - 1.49 (m, 14H), 1.48 - 1.35 (m, 4H), 1.22 - 0.91 (m, 9H), 0.53 (s, 3H).

[0410] Synthetic Example A69: S-((3S,8S,9S,10R,13S,14S,17R)-17-((E)-7-methoxyheptane-2- (en-2-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecano-1H-cyclopentane[a] phenanthrene-3-yl) ethioester

[0411] Synthetic Example A68 (0.30 g, 0.63 mmol) and potassium thioacetate (KSAc, 0.18 g, 1.57 mmol) were dissolved in dimethylformamide (DMF, 4 mL) at room temperature. The reaction mixture was stirred at 85 °C for 3 hours. After the reaction was complete, the reaction mixture was cooled to ambient temperature and purified with a saturated aqueous sodium bicarbonate solution. The resulting mixture was extracted twice with ethyl acetate. The resulting organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure. The residue was purified by silica gel column chromatography to give the desired compound A69 (0.19 g, 67% yield).

[0412] 1 H NMR(500 MHz, CDCl3) δ 5.32 (dt, J1 = 5.3 Hz, J2 = 2.1 Hz, 1H), 5.20- 5.14 (m, 1H), 4.03 - 3.97 (m, 1H), 3.37 (t, J = 6.6 Hz, 4H), 3.33 (s, 5H),2.81 - 2.73 (m, 1H), 2.32 - 2.26 (m, 5H), 2.11 - 1.94 (m, 8H), 1.85 - 1.49(m, 23H), 1.48 - 1.36 (m, 6H), 1.33 - 0.98 (m, 13H), 0.56 (d, J = 18.0 Hz, 5H).

[0413] Synthesis Example A70: (3S, 8S, 9S, 10R, 13S, 14S, 17R)-17-((E)-7-methoxyhept-2-ene- 2-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecano-1H-cyclopentane[a] phenanthrene-3-thiol

[0414] The synthetic compound A70 (0.19 g, 0.42 mmol) was dissolved in methanol (4 mL), and sodium methoxide (NaOMe, 0.34 g, 0.63 mmol) was added at 0 °C. The reaction mixture was stirred for 3 hours. The reaction was brought to completion with 1 N hydrochloric acid aqueous solution, and the reaction mixture was extracted twice with ethyl acetate. The resulting organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure. The residue was purified by silica gel column chromatography to give the desired compound A70 (8.0 mg, 4.5% yield).

[0415] 1H NMR(500 MHz, CDCl3) δ 5.34 (dt, J1 = 4.7 Hz, J2 = 2.0 Hz, 1H), 5.22- 5.13 (m, 1H), 3.51 (tt, J1 = 11.1 Hz, J2 = 4.6 Hz, 1H), 3.36 (t, J = 6.7 Hz,2H), 3.32 (s, 3H), 2.37 - 2.17 (m, 2H), 2.11 - 1.93 (m, 5H), 1.88 - 1.73 (m,5H), 1.71 - 1.34 (m, 29H), 1.34 - 0.80 (m, 16H), 0.53 (s, 3H).

[0416] Examples 1-7:

[0417] Option 1-7

[0418]

[0419] Synthetic Example A71: (E)-6-((3S,8S,9S,10R,13S,14S,17R)-10,13-dimethyl-3- (methanesulfonyloxy)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecano-1H-cyclopentan[a]phenanthrene-17- Methyl hepta-5-enoate

[0420] Synthesis Example A71 was prepared from starting material synthesis Example A47 using the same method as described in Synthesis Example A68.

[0421] 1 H NMR(500 MHz, CDCl3) δ 5.43 (d, J = 5.2 Hz, 1H), 5.15 (t, J = 7.1Hz, 1H), 4.53 (tt, J1 = 11.0 Hz, J2 = 5.0 Hz, 1H), 3.67 (s, 3H), 3.01 (s, 3H),2.58 - 2.46 (m, 2H), 2.31 (t, J = 7.6 Hz, 2H), 2.11 - 1.97 (m, 6H), 1.91 (dt,J1 = 13.5 Hz, J2 = 3.6 Hz, 1H), 1.85 - 1.74 (m, 3H), 1.73 - 1.50 (m, 17H),1.44 (dd, J1 = 10.1 Hz, J2 = 4.8 Hz, 3H), 1.23 - 0.82 (m, 12H), 0.54 (s, 3H).

[0422] Synthetic Example A72: (E)-6- ((3S, 8S, 9S, 10R, 13S, 14S, 17R)-3- (acetylthio)- 10,13-Dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecano-1H-cyclopentan[a]phenanthrene-17-yl) Methyl hepta-5-enoate

[0423] Synthesis Example A72 was prepared according to the same method described in Synthesis Example A69.

[0424] 1 H NMR(500 MHz, CDCl3) δ 5.31 (dt, J1 = 4.4 Hz, J2 = 2.0 Hz, 1H), 5.17- 5.11 (m, 1H), 3.99 (s, 1H), 3.66 (s, 3H), 2.76 (d, J = 14.7 Hz, 1H), 2.29(d, J = 10.6 Hz, 5H), 2.10 - 1.93 (m, 6H), 1.82 - 1.48 (m, 19H), 1.46 - 1.01(m, 8H), 0.99 (s, 3H), 0.53 (s, 3H).

[0425] Synthetic Example A73: (E)-6-((3S,8S,9S,10R,13S,14S,17R)-3-mercapto-10,13-dimethyl 2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecanoic acid-1H-cyclopentan[a]phenanthrene-17-yl)hept-5-enoic acid Methyl ester

[0426] Synthesis Example A73 was prepared according to the same method described in Synthesis Example A70.

[0427] 1 H NMR(500 MHz, CDCl3) δ 5.38 (dt, J1 = 4.7 Hz, J2 = 2.0 Hz, 1H), 5.19- 5.12 (m, 1H), 3.67 (s, 3H), 3.44 - 3.37 (m, 1H), 2.87 - 2.78 (m, 1H), 2.35- 2.28 (m, 2H), 2.12 - 1.96 (m, 6H), 1.85 - 1.76 (m, 2H), 1.74 - 1.52 (m,16H), 1.49 - 1.35 (m, 2H), 1.24 - 1.05 (m, 4H), 0.99 (s, 3H), 0.55 (s, 3H).

[0428] Examples 1-8:

[0429] Option 1-8

[0430]

[0431] Synthetic Example A74: (E)-3-((3S,8S,9S,10R,13S,14S,17R)-10,13-dimethyl-3- ((tetrahydro-2H-pyran-2-yl)oxy)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecano-1H-cyclopentane [a]phenanthrene-17-yl)-N-methoxy-N-methylbut-2-enamide

[0432] At -5°C, after purging with nitrogen, 0.20 g (0.44 mmol) of Synthetic Example A6 and N,O-dimethylhydroxylamine hydrochloride (85 mg, 0.88 mmol) were dissolved in tetrahydrofuran (THF, 2 mL). Then, isopropyl magnesium bromide (i-PrMgBr, 2.3 mL, 0.75 M THF solution, 1.75 mmol) was added dropwise, and the reaction mixture was stirred at -5°C for 2 hours. The reaction was brought to completion with saturated ammonium chloride aqueous solution, and the reaction mixture was extracted twice with ethyl acetate. The resulting organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure. The residue was purified by silica gel column chromatography to give the desired compound A74 (0.15 g, 73% yield).

[0433] 1 H NMR(500 MHz, CDCl3) δ 6.13 (s, 1H), 5.35 (dd, J1 = 8.0 Hz, J2 = 5.7Hz, 1H), 4.72 (dd, J1 = 5.0 Hz, J2 = 2.7 Hz, 1H), 3.92 (ddd, J1 = 10.7 Hz, J2= 7.0 Hz, J3 = 3.3 Hz, 1H), 3.67 (s, 3H), 3.58 - 3.45 (m, 2H), 3.21 (s, 3H), 2.43 - 2.31 (m, 2H), 2.20 (t, J = 9.3 Hz, 1H), 2.13 (d, J = 1.3 Hz, 3H), 2.03- 1.97 (m, 1H), 1.94 - 1.79 (m, 5H), 1.73 (ddt, J1 = 13.0 Hz, J2 = 8.8 Hz, J3= 3.9 Hz, 3H), 1.63 - 1.39 (m, 12H), 1.34 - 1.21 (m, 2H), 1.20 - 1.03 (m,2H), 1.03 - 0.93 (m, 4H), 0.63 (s, 3H).

[0434] Synthetic Example A75: (E)-5- ((3S,8S,9S,10R,13S,14S,17R)-10,13-dimethyl-3- ((tetrahydro-2H-pyran-2-yl)oxy)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecano-1H-cyclopentane [a]phenanthrene-17-yl)hex-4-en-3-one

[0435] At -5°C, after purging with nitrogen, 0.96 g (0.20 mmol) of synthetic example A74 was dissolved in tetrahydrofuran (THF, 1 mL), followed by dropwise addition of ethyl magnesium bromide (EtMgBr, 0.4 mL, 0.9 M THF solution, 0.40 mmol), and the reaction mixture was stirred at -5°C for 3 hours. The reaction was brought to completion with saturated ammonium chloride aqueous solution, and the reaction mixture was extracted twice with ethyl acetate. The resulting organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure. The residue was purified by silica gel column chromatography to give the desired compound A75 (0.15 g, 73% yield).

[0436] 1 H NMR(500 MHz, CDCl3) δ 6.08 (d, J = 1.5 Hz, 1H), 5.35 (t, J = 7.0Hz, 1H), 4.72 (t, J = 3.9 Hz, 1H), 3.97 - 3.87 (m, 1H), 3.59 - 3.44 (m, 2H),2.46 (q, J = 7.4 Hz, 2H), 2.39 - 2.30 (m, 2H), 2.23 - 2.12 (m, 5H), 2.04 -1.96 (m, 1H), 1.95 - 1.79 (m, 6H), 1.77 - 1.66 (m, 3H), 1.55 (s, 19H), 1.26(td, J1 = 12.3 Hz, J2 = 4.8 Hz, 3H), 1.21 - 0.93 (m, 11H), 0.59 (s, 3H).

[0437] Synthetic Example A76: (E)-5-((3S,8S,9S,10R,13S,14S,17R)-3-hydroxy-10,13-dimethyl 2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecano-1H-cyclopentan[a]phenanthrene-17-yl)hex-4-ene-3- ketone

[0438] This synthetic example A76 was prepared according to general method 3a.

[0439] 1H NMR(500 MHz, CDCl3) δ 6.08 (d, J = 1.2 Hz, 1H), 5.39 - 5.33 (m,1H), 3.53 (dq, J1 = 11.2 Hz, J2 = 5.6 Hz, 1H), 2.49 - 2.42 (m, 2H), 2.35 -2.12 (m, 7H), 2.06 - 1.96 (m, 1H), 1.92 - 1.79 (m, 5H), 1.77 - 1.68 (m, 2H), 1.54 (s, 17H), 1.32 - 1.21 (m, 3H), 1.20 - 0.94 (m, 11H), 0.59 (s, 3H).

[0440] Examples 1-9 to 1-13. Preparation of Synthetic Examples 1-4 to 1-57

[0441] Examples 1-9:

[0442] Synthesis Examples 1-10

[0443]

[0444] General Method 4

[0445] The compounds from Synthetic Examples 1-3 (3.03 g, 7.56 mmol) and tri-O-acetyl-D-glucose (3.09 g, 11.34 mmol) were dissolved in anhydrous toluene (50 mL) and acetonitrile (25 mL). The reaction mixture was kept at 35 °C, and lithium nonafluoro-1-butylsulfonate (Li-NFBS, 115.7 mg, 0.38 mmol) and (S)-camphorsulfonic acid (17.6 mg, 0.38 mmol) were added. The reaction mixture was stirred for 5 hours. The reaction was brought to completion with saturated sodium bicarbonate solution, and the reaction mixture was extracted twice with ethyl acetate. The resulting organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure. The residue was purified by silica gel column chromatography to give the desired compounds 1-10 (1.89 g, 41% yield) as the oil phase.

[0446] 1H NMR(500 MHz, CDCl3) δ 5.96 - 5.79(m, 2H), 5.36 - 5.33(m, 1H), 5.29- 5.25(m, 1H), 5.21 - 5.15(m, 2H), 4.28 - 4.15(m, 3H), 3.64 - 3.52(m, 1H),3.36(t, J = 5.0 Hz, 2H), 3.32(s, 3H), 2.42 - 2.30(m, 2H), 2.08 - 1.96(m,14H), 1.67 - 1.32(m, 14H), 1.20 - 1.01(m, 4H), 1.01 - 0.91(m, 4H), 0.53(s,3H).

[0447] Synthesis Examples 1-16

[0448]

[0449] Synthetic Examples 1-16 were prepared from available starting materials according to General Method 4, as shown in the reaction schemes above.

[0450] Synthesis Examples 1-42

[0451]

[0452] Synthetic Examples 1-42 were prepared from available starting materials according to General Method 4, as shown in the reaction schemes above.

[0453] Synthesis Examples 1-22

[0454]

[0455] The compounds from Synthetic Examples 1-10 (100 mg, 0.16 mmol) were dissolved in methanol (3 mL) and sodium hydroxide (26.1 mg, 0.65 mmol) was added. The reaction mixture was stirred at ambient temperature for 15.5 hours. The reaction was brought to completion with saturated sodium bicarbonate solution, and the reaction mixture was extracted twice with ethyl acetate. The resulting organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure. The residue was purified by silica gel column chromatography to give the desired compounds 1-22 (51.9 mg, 60% yield).

[0456] 1H NMR(500 MHz, CDCl3) δ 5.94(dt, J1= 6.3 Hz, J2= 3.3 Hz, 1H), 5.74(dt, J1= 6.2 Hz, J2= 3.3 Hz, 1H), 5.35(d, J = 5.0 Hz, 1H), 5.16(t, J = 7.5Hz, 1H), 5.12(t, J = 2.5 Hz, 1H), 4.21(dt, J1= 8.7 Hz, J2= 1.7 Hz, 1H), 3.90- 3.82(m, 2H), 3.78 - 3.75(m, 1H), 3.56 - 3.50(m, 1H), 3.34(t, J = 10.1 Hz,2H), 3.32(s, 3H), 2.39 - 2.30(m, 2H), 2.06 - 1.74(m, 11H), 1.67 - 1.36(m,13H), 1.20 - 0.91(m, 8H), 0.53(s, 3H).

[0457] Synthesis Examples 1-24

[0458]

[0459] The compounds from Synthetic Examples 1-22 (207.8 mg, 0.39 mmol) were dissolved in tetrahydrofuran (THF, 5 mL), and triethylamine (TEA, 0.27 mL, 1.97 mmol) and dimethylphosphonic chloride (132.6 mg, 1.18 mmol) were added at 0 °C. The reaction mixture was stirred for 19 hours. After the reaction was complete with water, the mixture was extracted twice with ethyl acetate. The resulting organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure. The residue was purified by silica gel column chromatography to give the desired compounds 1-24 (8.9 mg, 3% yield). 1H NMR(500 MHz, CDCl3) δ 6.07(d, J = 10.1 Hz,1H), 5.80 - 5.77(m, 1H), 5.33 - 5.32(m, 1H), 5.17 - 5.15(m, 2H), 4.90 - 4.86(m, 1H), 4.25 - 4.21(m, 1H), 4.17 - 4.13(m, 1H), 4.08 - 4.05(m, 1H), 3.57 -3.51(m, 1H), 3.36(t, J = 7.5 Hz, 2H), 3.31(s, 3H), 2.35 - 2.29(m, 2H), 2.06 -1.96(m, 4H), 1.87 - 1.76 (m, 4H), 1.67 - 1.24 (m, 24H), 1.19 - 0.84 (m, 10H), 0.53 (s, 3H).

[0460] Synthesis Examples 1-44

[0461]

[0462] Synthesis Example A84: (2R, 3S) -6- (((3S, 8S, 9S, 10R, 13S, 14S, 17R) -17- ((E) -7- Methoxyhept-2-en-2-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecano- 1H-Cyclopentan[a]phenanthrene-3-yl)oxy)-2-(((methanesulfonyloxy)methyl)-3,6-dihydro-2H-pyran-3-yl)methanesulfonyl esters

[0463] The compounds from Synthetic Examples 1-22 (0.38 g, 0.72 mmol) were dissolved in tetrahydrofuran (THF, 7 mL), and triethylamine (TEA, 0.6 mL, 4.29 mmol) and methanesulfonyl chloride (MsCl, 0.20 mL, 2.86 mmol) were added at 0 °C. The reaction mixture was then stirred for 3 hours. The reaction was brought to a complete stop with saturated sodium bicarbonate solution, and the reaction mixture was extracted twice with ethyl acetate. The resulting organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure. The residue was purified by silica gel column chromatography to give the desired compound A84 (0.44 g, 90% yield).

[0464] 1H NMR (500 MHz, CDCl3) δ 6.07 - 6.01 (m, 1H), 5.88 (ddd, J1 = 10.2 Hz, J2 = 2.8 Hz, J3 = 1.9 Hz, 1H), 5.38 (d, J = 5.1 Hz, 1H), 5.23 - 5.13 (m, 3H), 4.43 (qd, J1 = 11.3 Hz, J2 = 3.3 Hz, 2H), 4.23 (ddd, J1 = 9.4 Hz, J2 = 4.2 Hz, J3 = 2.4 Hz, 1H), 3.53 (tt, J1 = 10.2 Hz, J2 = 5.0 Hz, 1H), 3.36 (t, J = 6.6Hz, 2H), 3.32 (s, 3H), 3.09 (s, 3H), 3.07 (s, 3H), 2.39 - 2.29 (m, 2H), 2.09- 1.94 (m, 4H), 1.91 - 1.74 (m, 4H), 1.70 - 1.35 (m, 25H), 1.21 - 0.89 (m,9H), 0.53 (s, 3H).

[0465] Synthetic Examples 1-44: S-(((2R,3R)-3-(acetylthio)-6-(((3S,8S,9S,10R,13S, 14S,17R)-17- ((E)-7-methoxyhept-2-en-2-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12, 13,14,15,16,17-Tetradecano-1H-cyclopentan[a]phenanthrene-3-yl)oxy)-3,6-dihydro-2H-pyran-2-yl)methyl) Ethioester

[0466] Synthetic Example A84 (0.2 g, 0.29 mmol) and potassium thioacetate (KSAc, 0.2 g, 1.75 mmol) were dissolved in dimethylformamide (DMF, 1.5 mL) at room temperature. The reaction mixture was then stirred at 85 °C for 2 hours. After the reaction was complete, the reaction mixture was cooled to room temperature and the reaction was terminated with a saturated aqueous sodium bicarbonate solution. The resulting mixture was extracted twice with ethyl acetate. The resulting organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure. The residue was purified by silica gel column chromatography to give the desired compound 1-44 (63 mg, 34% yield).

[0467] 1H NMR(500 MHz, CDCl3) δ 6.03 (dd, J1 = 9.8 Hz, J2 = 5.9 Hz, 1H), 5.80- 5.74 (m, 1H), 5.40 (d, J = 5.3 Hz, 1H), 5.18 (t, J = 7.0 Hz, 1H), 5.11 (d,J = 2.9 Hz, 1H), 4.37 - 4.30 (m, 1H), 4.19 - 4.14 (m, 1H), 3.61 (td, J1 =11.3 Hz, J2 = 5.6 Hz, 1H), 3.37 (t, J = 6.6 Hz, 2H), 3.33 (s, 3H), 3.10 -3.06 (m, 2H), 2.35 (d, J = 20.4 Hz, 9H), 2.09 - 1.97 (m, 8H), 1.91 - 1.75 (m,4H), 1.70 - 1.37 (m, 39H), 1.23 - 0.92 (m, 9H), 0.54 (s, 3H).

[0468] Examples 1-13:

[0469] Option 1-13

[0470]

[0471] Synthetic Examples 1-56: 2-(((3S,8S,9S,10R,13S,14S,17R)-17-((E)-7-methoxyheptane- 2-en-2-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecano-1H-cyclopentane[ a]phenanthrene-3-yl)oxyethyl acetate

[0472] Synthetic Example A47 (1.5 g, 3.74 mmol) was dissolved in dichloromethane (50 mL), and Rh2(OAc)4 (33.1 mg, 0.08 mmol) was added at ambient temperature. The reaction mixture was stirred at ambient temperature for 15 minutes. Ethyl 2-diazoethyl acetate (15%, in toluene, 3.4 mL) was slowly added dropwise, and the reaction mixture was stirred at ambient temperature for 4 hours. The reaction was allowed to proceed with water, and the mixture was extracted twice with dichloromethane. The resulting organic layer was dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure. The residue was purified by silica gel column chromatography to give the desired compound 1-56 (1.2 g, 67.4% yield).

[0473] 1H NMR(500 MHz, CDCl3) δ 10.07(d, J = 7.9 Hz, 1H), 5.93(dq, J1 = 8.0Hz, J2= 1.2 Hz, 1H), 5.36-5.33(m, 1H), 4.72(dd, J1 = 5.0 Hz, J2 = 2.8 Hz,1H), 3.89 - 3.84(m, 1H), 3.59 - 3.41(m, 3H), 2.32 - 2.37(m, 2H), 2.27 - 2.16(m, 5H), 2.08 - 1.95(m, 2H), 1.94 - 1.79(m, 6H), 1.79 - 1.67(m, 4H), 1.66 -1.37(m, 14H), 1.35 - 1.23(m, 3H), 1.22 - 1.16(m,1H), 1.12 - 1.04(m, 1H), 1.03- 0.91(m, 6H), 0.62(s, 3H).

[0474] Synthetic Examples 1-57: 2-(((3S,8S,9S,10R,13S,14S,17R)-17-((E)-7-methoxyheptane- 2-en-2-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecano-1H-cyclopentane[ a]phenanthrene-3-yl)oxy)acetic acid

[0475] The compounds from Synthetic Examples 1-56 (1.0 g, 2.05 mmol) were dissolved in 20 mL of THF, and an aqueous solution of NaOH (328.7 mg, 8.22 mmol) was added at room temperature. The reaction mixture was then stirred for 3 hours. The reaction was brought to completion by acidification with 1N hydrochloric acid, and the reaction mixture was extracted twice with ethyl acetate. The resulting organic layer was dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure. The residue was purified by silica gel column chromatography to give the desired compounds 1-57 (931.0 mg, 98.8% yield).

[0476] 1H NMR(500 MHz, CDCl3) δ 5.38 (dd, J = 5.0, 2.5 Hz, 1H), 5.22 - 5.14(m, 1H), 4.13 (s, 2H), 3.38 (t, J = 6.7 Hz, 2H), 3.33 (s, 4H), 2.38 (ddd, J =13.2, 4.9, 2.3 Hz, 1H), 2.33 - 2.24 (m, 1H), 2.09 - 1.96 (m, 4H), 1.91 (ddt,J = 16.9, 13.3, 3.6 Hz, 2H), 1.85 - 1.76 (m, 2H), 1.71 - 1.50 (m, 13H), 1.50- 1.34 (m, 5H), 1.18 (tt, J = 13.1, 5.6 Hz, 2H), 1.11 - 1.03 (m, 2H), 1.01(s, 3H), 0.95 (td, J = 11.6, 4.9 Hz, 1H), 0.55 (s, 3H).

[0477] Examples 1-14:

[0478] Preparation of Cu06-1004

[0479] Compound CU06-1004 is used synonymously with compound SAC-1004 and can be prepared by known methods. It can also be prepared in a manner similar to that shown in the above synthetic examples.

[0480]

[0481] The structures of the compounds described in the synthesis examples are shown below.

[0482] Table 5.

[0483]

[0484]

[0485]

[0486] The IUPAC names and analytical data of the compounds described in the synthesis examples are as follows.

[0487] Table 6.

[0488]

[0489]

[0490]

[0491]

[0492]

[0493]

[0494]

[0495]

[0496]

[0497]

[0498] Example 2:

[0499] The compounds of Synthetic Examples 2-1 to 2-3 and 2-7 were prepared according to Scheme 2-1 as shown below.

[0500] Option 2-1

[0501]

[0502] Synthesis Example 2-1:

[0503] Synthesis Example 2-1 was prepared by the same method as described in Synthesis Examples 1-22.

[0504] Synthesis Example 2-2:

[0505] Synthesis Example 2-1 was prepared by the same method as described in Synthesis Example A7.

[0506] Synthesis Examples 2-3 and 2-7:

[0507] Synthesis Example 2-1 was prepared by the same method as described in Synthesis Examples 1-24.

[0508] Synthesis Examples 2-4:

[0509] The compounds of Synthetic Examples 2-4 were prepared from Synthetic Example 2-2 according to Scheme 2-2 as shown below.

[0510] Option 2-2

[0511]

[0512] Synthetic Examples 2-4 were prepared according to General Method 1.

[0513] Synthesis Examples 2-5 and 2-6:

[0514] Synthetic Examples 2-5 and 2-6 were prepared from Synthetic Example 2-2 according to Scheme 2-3 as shown below.

[0515] Option 2-3

[0516]

[0517] Synthesis Example B1: (E)-6- ((3S, 8S, 9S, 10R, 13S, 14S, 17R)-3- (((5S, 6R)-5-methoxy 6-(methoxymethyl)-5,6-dihydro-2H-pyran-2-yl)oxy)-10,13-dimethyl-2,3,4,7,8,9,10, 11,12,13,14,15,16,17-Tetradecano-1H-cyclopentan[a]phenanthrene-17-yl)hept-5-en-1-ol

[0518] 1 H NMR(500 MHz, CDCl3) δ 6.07(d, J = 10.2 Hz, 1H), 5.78 - 5.71(m, 1H), 5.36(d, J = 4.8 Hz, 1H), 5.21 - 5.13(m, 2H), 3.90(d, J = 3.3 Hz, 2H), 3.69 -3.53(m, 5H), 3.43(s, 3H), 3.42 - 3.39(m, 3H), 2.45 - 2.28(m, 2H), 2.11 - 1.95(m, 4H), 1.82(dd, J1 = 31.7 Hz, J2 = 11.8 Hz, 4H), 1.71 - 1.38(m, 14H), 1.23 -0.90(m, 9H), 0.54(s, 3H). For C 35 H 55 O5 + MS(m / z) [M+H] + The calculated value is 543.40, and the measured value is 543.6.

[0519] Option 2-4

[0520]

[0521] Synthesis Example B2: (E) -6- ((3S, 8S, 9S, 10R, 13S, 14S, 17R) -3- (((5S, 6R) -6- (acetoxymethyl)-5-hydroxy-5,6-dihydro-2H-pyran-2-yl)oxy)-10,13-dimethyl-2,3,4,7,8,9, 10,11,12,13,14,15,16,17-Tetradecano-1H-cyclopentan[a]phenanthrene-17-yl)hept-5-enoic acid methyl ester

[0522] The product of Synthetic Example 2-2 (2.68 g, 4.94 mmol) was dissolved in tetrahydrofuran (THF, 15 mL), and pyridine (0.81 mL, 9.93 mmol) and acetic anhydride (Ac₂O, 4.94 mmol) were added at 0 °C. The reaction mixture was then stirred for 5 hours. After the reaction was complete, the reaction mixture was diluted with ethyl acetate and washed with saturated ammonium chloride aqueous solution and brine. The resulting organic layer was dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure. The residue was purified by silica gel column chromatography to give the desired compound B2 (1.47 g, 51% yield).

[0523] 1 H NMR(500 MHz, CDCl3) δ5.96(d, J = 12.7 Hz, 1H), 5.75(dd, J1 = 3.0,J2 = 12.7 Hz, 1H), 5.37(d, J = 6.3 Hz, 1H), 5.15 (t, J = 8.7 Hz, 1H), 4.52(dd, J1 = 6.3, J2 = 15.2 Hz, 1H), 4.27 (dd, J1 = 2.7, J2 = 15.1 Hz, 1H), 4.05(bs, 1H), 3.92 - 3.88(m, 1H), 3.67 (s, 3H), 3.60 - 3.56(m, 1H), 2.42 - 2.30(m, 4H), 2.13-1.98(m, 8H), 1.88-1.42(m, 16H), 1.21-0.92(m, 8H), 0.55(s,3H).

[0524] The names of the compounds and analytical data of the synthetic examples 2-1 to 2-7 are shown in Table 7.

[0525] Table 7.

[0526]

[0527]

[0528]

[0529]

[0530] Example 3:

[0531] Example 3-1: The process is carried out according to Scheme 3-1 shown below.

[0532] Option 3-1

[0533]

[0534] In scheme 3-1, Lv represents a leaving group, including, but not limited to, methanesulfonyl or p-toluenesulfonyl.

[0535] Step 1:

[0536] Synthetic Example C1. (E)-6-((3S,8S,9S,10R,13S,14S,17R)-10,13-dimethyl-3-((tetramethyl-3- ... 2H-pyran-2-yl)oxy)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecano-1H-cyclopentanol[a] ]Phenylacetyl-17-yl)hept-5-en-1-ylmethanesulfonate

[0537]

[0538] The compound from Synthetic Example 1-1 (3.0 g, 6.37 mmol) was dissolved in dimethylformamide (DMF, 70 mL), and triethylamine (TEA, 4.48 mL, 31.87 mmol) and methanesulfonyl chloride (MsCl, 1.48 mL, 19.12 mmol) were added at 0 °C. The reaction mixture was stirred for 3.5 hours. After the reaction was completed with water, the reaction mixture was extracted twice with ethyl acetate. The resulting organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure. The residue was purified by silica gel column chromatography to give the desired compound C1 (1.68 g, 48% yield).

[0539] 1 H NMR(500 MHz, CDCl3) δ 5.35 - 5.32(m, 1H), 5.14(t, J = 7.5 Hz, 1H), 4.71 - 4.70(m, 1H), 4.22(t, J = 5.0 Hz, 2H), 3.93 - 3.89(m, 1H), 3.55 - 3.45(m, 2H), 2.99(s, 3H), 2.37 - 2.31(m, 2H), 2.07(m, J = 6.7 Hz, 2H), 2.01 -1.95(m, 2H), 1.88 - 1.37(m, 24H), 1.20 - 1.12(m, 2H), 1.09 - 1.01(m, 2H), 1.00(2, 3H), 0.94(dt, J1= 15.0 Hz, J2= 5.0 Hz, 1H), 0.53(s, 3H).

[0540] Synthesis Example C2 was prepared in the same manner as Synthesis Example C1, except that p-toluenesulfonyl chloride (p-TsCl; p-Ts) was used instead of MsCl.

[0541] Step 2:

[0542] Synthetic Example C3.2- (((3S,8S,9S,10R,13S,14S,17R)-10,13-dimethyl-17- ((E)- 7- (((R)-tetrahydrofuran-3-yl)oxy)hept-2-en-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,16, 17-Tetradecano-1H-cyclopentan[α]phenanthrene-3-yl)oxy)tetrahydro-2H-pyran

[0543]

[0544] The compound from Synthetic Example C1 (519.1 mg, 0.95 mmol) was dissolved in dimethylformamide (DMF, 9.5 mL), and sodium hydride (NaH, 90.8 mg, 2.27 mmol) was added dropwise at 0 °C. The reaction mixture was then stirred for 20 minutes. (R)-tetrahydrofuran-3-ol (100 mg, 1.14 mmol) was slowly added to the reaction mixture, and the mixture was stirred at 40 °C for 16.5 hours. After the reaction was completed with water, the reaction mixture was extracted with ethyl acetate, washed with water and brine, and the resulting organic layer was dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure. The residue was purified by silica gel column chromatography to give the desired compound, Synthetic Example C3 (287.6 mg, 56% yield).

[0545] 1 H NMR(500 MHz, CDCl3) δ 5.35 - 5.33(m, 1H), 5.17 - 5.14(m, 1H), 4.71- 4.70(m, 1H), 4.08 - 4.05(m, 1H), 3.92 - 3.86(m, 2H), 3.81 - 3.77(m, 3H),3.53 - 3.46(m, 2H), 3.42 - 3.35(m, 2H), 2.35 - 2.31(m, 2H), 2.06 - 1.94(m,6H), 1.88 - 1.36(m, 24H), 1.19 - 1.12(m, 2H), 1.08 - 1.02(m, 2H), 1.00(s,3H), 0.94(dt, J1 = 12.5 Hz, J2 = 5.0 Hz, 1H), 0.53(s, 3H).

[0546] Synthetic Examples C4 to C6, C11 to C15 and C39 to C40 were prepared in the same manner.

[0547] Step 3:

[0548] Synthetic Example C19. (3S, 8S, 9S, 10R, 13S, 14S, 17R)-10,13-dimethyl-17-((E)-7- (((R)-tetrahydrofuran-3-yl)oxy)hept-2-en-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17- Tetradecano-1H-cyclopentan[a]phenanthrene-3-ol

[0549]

[0550] Synthesis Example C19 was prepared according to general method 3a.

[0551] 1 H NMR(500 MHz, CDCl3) δ 5.35 - 5.33(m, 1H), 5.17 - 5.14(m, 1H), 4.08- 4.05(m, 1H), 3.90 - 3.85(m, 1H), 3.81 - 3.77(m, 3H), 3.54 - 3.48(m, 1H),3.42 - 3.34(m, 2H), 2.32 - 2.27(m, 1H), 2.26 - 2.19(m, 1H), 2.06 - 1.94(m,6H), 1.86 - 1.76(m, 4H), 1.68 - 4.36(m, 15H), 1.20 - 1.12(m, 2H), 1.11 - 1.04(m, 2H), 1.00(s, 3H), 0.98 - 0.92(m, 1H), 0.53(s, 3H).

[0552] Synthetic Examples C20 to C24, C29 to C33 and C37 were prepared in the same manner.

[0553] Step 4:

[0554] Synthetic Examples C38, 3-1 to 3-6, 3-11 to 3-15 were prepared according to General Method 4.

[0555] Synthetic Example C38. ((2R,3S)-3-acetoxy-6- (((3S,8S,9S,10R,13S,14S,17R)- 10,13-Dimethyl-17-((E)-7-(toluenesulfonyloxy)hept-2-en-2-yl)-2,3,4,7,8,9,10,11,12, 13,14,15,16,17-Tetradecano-1H-cyclopentan[a]phenanthrene-3-yl)oxy)-3,6-dihydro-2H-pyran-2-yl)acetic acid methyl ester

[0556]

[0557] 1H NMR(500 MHz, CDCl3) δ 7.79(d, J = 8.3 Hz, 2H), 7.36 - 7.32(m, 2H), 5.89 - 5.80(m, 2H), 5.36(d, J = 5.3 Hz, 1H), 5.32 - 5.28(m, 1H), 5.18(s, 1H),5.08(t, J = 7.0 Hz, 1H), 4.27 - 4.15(m, 3H), 4.03(t, J = 6.5 Hz, 2H), 3.56(tt, J1 = 10.6 Hz, J2 = 4.7 Hz, 1H), 2.45(s, 3H), 2.44 - 2.31(m, 2H), 2.09(d,J = 7.8 Hz, 6H), 1.98(q, J = 7.4 Hz, 4H), 1.87(d, J = 13.5 Hz, 2H), 1.77(d, J= 12.7 Hz, 2H), 1.66 - 1.51(m, 10H), 1.47 - 1.35(m, 4H), 1.17(td, J1 = 12.4Hz, J2 = 5.9 Hz, 2H), 1.10 - 0.99(m, 5H), 0.95(td, J1 = 11.7 Hz, J2 = 4.7 Hz, 1H), 0.52(s, 3H). For C 43 H 64 O9SN + MS(m / z) [M+NH4) + The calculated value is 770.40, and the measured value is 770.6.

[0558] Table 8.

[0559]

[0560] Example 3-2:

[0561] Option 3-2

[0562]

[0563] In scheme 3-2, R 5a For H, R 5b For Me, R 4 It is a methanesulfonyl or acetyl group.

[0564] Synthetic Example C7: N-((E)-6-((3S,8S,9S,10R,13S,14S,17R)-10,13-dimethyl-3- ((tetrahydro-2H-pyran-2-yl)oxy)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecano-1H-cyclopentane [a]phenanthrene-17-yl)hept-5-en-1-yl)methanesulfonamide

[0565]

[0566] Except for the use of methanesulfonamide, synthesis example C7 was prepared according to general method 2.

[0567] 1 H NMR(500 MHz, CDCl3) δ 5.35(t, J = 6.7 Hz, 1H), 5.14(t, J = 7.0 Hz,1H), 4.72(d, J = 4.5 Hz, 1H), 4.15(t, J = 6.2 Hz, 1H), 3.96 - 3.89(m, 1H),3.58 - 3.45(m, 2H), 3.14(q, J = 6.9 Hz, 2H), 2.96(s, 3H), 2.36(d, J = 7.3 Hz,2H), 2.07(q, J = 7.2 Hz, 2H), 2.00(q, J = 7.6 Hz, 2H), 1.90 - 1.51(m, 20H), 1.46 - 1.39 (m, 4H), 1.22 - 1.13 (m, 2H), 1.10 - 1.03 (m, 2H), 1.01 (s, 3H), 0.95 (td, J1 = 11.7, J2 = 4.7 Hz, 1H), 0.54 (s, 3H). For C 32 H 53 NO4S + MS(m / z) [M+H] + The calculated value is 548.37, and the measured value is 548.4.

[0568] Synthetic Example C25: N-((E)-6-((3S,8S,9S,10R,13S,14S,17R)-3-hydroxy-10,13- Dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecano-1H-cyclopentan[a]phenanthrene-17-yl)heptane-5- (en-1-yl)methanesulfonamide

[0569]

[0570] Synthesis Example C25 was prepared according to General Method 3a.

[0571] For C 27 H 46 NO3S + MS(m / z) [M+H] + The calculated value is 464.31, and the measured value is 464.3. Synthesis Example 3- 7: ((2R,3S)-3-acetoxy-6- (((3S,8S,9S,10R,13S,14S,17R)-10,13-dimethyl-17- ((E)) -7-(methylsulfonylamino)hept-2-en-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecano- 1H-Cyclopentan[a]phenanthrene-3-yl)oxy)-3,6-dihydro-2H-pyran-2-yl)acetic acid methyl ester

[0572] Synthetic Examples 3-7 were prepared according to General Method 4.

[0573] Synthesis Examples 3-8 to 3-10

[0574] Synthetic Examples 3-8 to 3-10 were prepared according to General Method 4.

[0575] Table 9.

[0576]

[0577] Example 3-3:

[0578] Option 3-3

[0579]

[0580] In scheme 3-3, R 4 It is methylthio, ethylthio, or methanesulfonyl.

[0581] Table 10.

[0582]

[0583] Synthetic Example C16. 2-(((3S,8S,9S,10R,13S,14S,17R)-10,13-dimethyl-17-((E)) -7-(methylthio)hept-2-en-2-yl) -2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecano-1H-cyclopentane [a]phenanthrene-3-yl)oxy)tetrahydro-2H-pyran

[0584] Synthetic Example C2 (200 mg, 0.32 mmol) was dissolved in dimethylformamide (DMF, 5 mL), and sodium thiomethoxide (NaSMe, 36 mg, 0.48 mmol) was added dropwise at 0 °C. The reaction mixture was then stirred at ambient temperature for 1 hour. After the reaction was completed with water, the reaction mixture was extracted twice with ethyl acetate. The resulting organic layer was dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure. The residue was purified by silica gel column chromatography to give the desired compound C16 (70.8 mg, 44% yield).

[0585] Synthetic Example C18. 2-(((3S,8S,9S,10R,13S,14S,17R)-10,13-dimethyl-17-((E)) -7-(methylsulfonyl)hept-2-en-2-yl) -2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecano-1H- Cyclopentan[α]phenanthrene-3-yl)oxy)tetrahydro-2H-pyran

[0586] Synthetic Example C2 (100 mg, 0.16 mmol), sodium methanesulfonate (NaSO2Me, 50 mg, 0.48 mmol), and potassium iodide (KI, 80 mg, 0.48 mmol) were dissolved in dimethylformamide (DMF, 2 mL). The reaction mixture was stirred at 120 °C for 2 hours. The mixture was diluted with ethyl acetate and washed with brine. The resulting organic layer was then dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure. The residue was purified by silica gel column chromatography to give the desired compound C18 (64 mg, 75% yield).

[0587] Examples 3-4:

[0588] Option 3-4

[0589] Synthesis Examples 3-19 to 3-24

[0590] Synthetic Examples 3-19 to 3-24 were prepared from Synthetic Example C38 using different reactants according to General Method 2.

[0591] Tables 11 and 12 list the structures, compound names, and analytical data for synthetic examples 3-1 to 3-24. Table 11.

[0592]

[0593]

[0594] Table 12.

[0595]

[0596]

[0597]

[0598]

[0599]

[0600]

[0601]

[0602]

[0603] Example 4:

[0604] Example 4-1:

[0605] Option 4-1

[0606]

[0607] In scheme 4-1, R 4 and / or R 5 It is either hydrogen or methyl.

[0608] Table 13.

[0609]

[0610] Synthetic Example D15: (E)-6-((3S,8S,9S,10R,13S,14S,17R)-10,13-dimethyl-3- ((tetrahydro-2H-pyran-2-yl)oxy)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecano-1H-cyclopentane [a]phenanthrene-17-yl)-N-methylhept-5-enamide

[0611]

[0612] Synthetic Example A4 (240 mg, 0.50 mmol) and triethylamine (TEA, 104 μL, 0.74 mmol) were dissolved in tetrahydrofuran (THF, 15 mL). Isobutyl chloroformate (100 μL, 0.75 mmol) was then added at 0 °C, and the reaction mixture was stirred for 20 min. A methylamine solution (600 μL, 2 mol / L THF solution, 38.5 mmol) was added dropwise, and the reaction mixture was stirred at ambient temperature for 1 h. After the reaction was complete with saturated ammonium chloride aqueous solution, the resulting solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure. The residue was purified by silica gel column chromatography to give the desired compound D15 (220 mg, 88% yield).

[0613] 1 H NMR(500 MHz, CDCl3) δ 5.40(brs, 1H), 5.36(d, J = 5.7 Hz, 1H), 5.17- 5.13(m, 1H), 4.74 - 4.69(m, 1H), 3.95 - 3.89(m, 1H), 3.57 - 3.44(m, 2H),2.81(d, J = 4.8 Hz, 3H), 2.36(d, J = 7.5 Hz, 2H), 2.20 - 2.15(m, 2H), 2.07(dd, J1 = 14.5 Hz, J2 = 7.2 Hz, 2H), 2.03 - 1.94(m, 2H), 1.91 - 1.60(m, 14H),1.58 - 1.53(m, 5H), 1.47 - 1.40(m, 3H), 1.20 - 1.15(m, 2H), 1.10 - 1.02(m,2H), 1.01(s, 3H), 0.98 - 0.92(m, 1H), 0.54(s, 3H).

[0614] Synthesis Examples D16 and D17 Prepared according to the same method described in synthesis example D15.

[0615] Synthesis Examples D18 to D20 Prepared according to general method 3a.

[0616] Synthesis Examples 4-5 to 4-7 Prepared according to general method 4.

[0617] Example 4-2:

[0618] Option 4-2

[0619]

[0620] Synthesis Example 4-1 was prepared from Synthesis Example A8 in the same manner as Scheme 4-2.

[0621] Synthesis Example 4-2 was prepared from Synthesis Example A9 in the same manner as in Process 4-1.

[0622] Synthetic Example D1: (E)-6-((3S,8S,9S,10R,13S,14S,17R)-10,13-dimethyl-3-((tetramethyl-3- ... 2H-pyran-2-yl)oxy)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecano-1H-cyclopentanol[a] ]Phenylacetyl-17-yl)-N-methoxy-N-methylhept-5-enamide

[0623] Synthetic Example A8 (1.98 g, 3.96 mmol) was dissolved in tetrahydrofuran (THF, 20 mL) and water (4 mL). Then, 1N lithium hydroxide (LiOH, 7 mL, 7.93 mmol) was added dropwise to the reaction mixture at room temperature. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, it was extracted with 1N hydrochloric acid aqueous solution and then with ethyl acetate. The resulting organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated by vacuum distillation. The resulting residue (230 mg, 0.47 mmol) was dissolved in dichloromethane (DCM, 3 mL), and N,O-dimethylhydroxylamine hydrochloride (55 mg, 0.54 mmol), hydroxybenzotriazole (HOBt, 76 mg, 0.56 mmol), N-methyl-2-pyrrolidone (NMP, 130 μL, 1.18 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI·HCl, 108 mg, 0.56 mmol) were added at 0 °C. The reaction mixture was then stirred at room temperature for 3 days. After the reaction was complete with water, the mixture was diluted with dichloromethane and extracted twice with dichloromethane. The resulting organic layer was dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure. The residue was purified by silica gel column chromatography to give the target compound D1 (223 mg).

[0624] 1H NMR(500 MHz, CDCl3) δ 5.36(t, J = 4.0 Hz, 1H), 5.21 - 5.16(m, 1H), 4.73 - 4.70(m, 1H), 3.92(td, J1 = 7.3 Hz, J2 = 3.4 Hz, 1H), 3.68(s, 3H), 3.58- 3.45(m, 2H), 3.18(s, 3H), 2.45 - 2.32(m, 3H), 2.10(q, J = 7.3 Hz, 2H), 2.03- 1.96(m, 2H), 1.93 - 1.76(m, 5H), 1.75 - 1.50(m, 14H), 1.49 - 1.40(m, 2H),1.22 - 1.13(m, 2H), 1.10 - 1.03(m, 2H), 1.01(s, 3H), 0.95(td, J1 = 11.7 Hz, J2= 4.8 Hz, 1H), 0.54(s, 3H).

[0625] Synthetic Example D4: (E)-8-((3S,8S,9S,10R,13S,14S,17R)-10,13-dimethyl-3-((tetramethyl-3- ... 2H-pyran-2-yl)oxy)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecano-1H-cyclopentanol[a] ]Phenylen-17-yl)non-7-en-3-one

[0626] Synthetic Example D1 (200 mg, 0.41 mmol) was dissolved in tetrahydrofuran (THF, 4 mL) at 0 °C, followed by dropwise addition of ethyl magnesium bromide (EtMgBr, 166 μL, 0.41 mmol), and the reaction mixture was stirred at ambient temperature for 16 hours. The reaction was completed by adding the reaction mixture to a saturated aqueous ammonium chloride solution, followed by extraction twice with ethyl acetate. The resulting organic layer was dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure. The residue was purified by silica gel column chromatography to give the desired compound D4 (176 mg, 85% yield).

[0627] 1H NMR(500 MHz, CDCl3) δ 5.38 - 5.33(m, 1H), 5.15 - 5.13(m, 1H), 4.74- 4.70(m, 1H), 3.95 - 3.89(m, 1H), 3.56 - 3.47(m, 2H), 2.45 - 2.31(m, 6H),2.07 - 1.93(m, 4H), 1.92 - 1.49(m, 22H), 1.43(dt, J1 = 12.4 Hz, J2 = 4.6 Hz,3H), 1.20 - 1.15(m, 2H), 1.09 - 1.03(m, 5H), 1.01(s, 3H), 0.98 - 0.92(m, 1H), 0.54(s, 3H).

[0628] Example 4-3:

[0629] Option 4-3

[0630]

[0631] Synthesis Example D6: Synthesis Example D6 was prepared in the same manner as described in Synthesis Example D4.

[0632] Synthetic Example D7: (E)-7- ((3S,8S,9S,10R,13S,14S,17R)-10,13-dimethyl-3- ((tetramethyl-3- ... 2H-pyran-2-yl)oxy)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecano-1H-cyclopentanol[a] ]Phenylacetyl-17-yl)oct-6-en-2-ol

[0633] Synthetic Example D6 (200 mg, 0.41 mmol) was dissolved in methanol (5 mL), cooled to 0°C, and then sodium borohydride (20 mg, 0.54 mmol) was added. The reaction mixture was stirred at ambient temperature for 3 hours. After the reaction was completed with saturated ammonium chloride aqueous solution, the reaction mixture was distilled under reduced pressure. The resulting residue was extracted with ethyl acetate, the resulting organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The organic layer obtained by reduced pressure distillation and the resulting residue were purified by silica gel column chromatography to give the desired compound D7 (198 mg, 96% yield). 1H NMR(500 MHz, CDCl3) δ 5.39 - 5.32(m, 1H),5.18(t, J = 7.1 Hz, 1H), 4.74 - 4.69(m, 1H), 3.96 - 3.88(m, 1H), 3.57 - 3.45(m, 2H), 2.39 - 2.30(m, 2H), 2.08 - 1.95(m, 2H), 1.93 - 1.76(m, 5H), 1.75 -1.51(m, 12H), 1.50 - 1.38(m, 7H), 1.28 - 1.24(m, 1H), 1.21(s, 6H), 1.20 -1.12(m, 3H), 1.11-1.03(m, 2H), 1.01(s, 3H), 0.99-0.91(m, 1H), 0.55(s,3H).

[0634] Synthetic Example D8: (E)-7-((3S,8S,9S,10R,13S,14S,17R)-10,13-dimethyl-3-((tetramethyl-3- ... 2H-pyran-2-yl)oxy)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecano-1H-cyclopentanol[a] ]Phenylacetyl-17-yl)-2-methyloct-6-en-2-ol

[0635] Synthetic Example D6 (270 mg, 0.56 mmol) was dissolved in tetrahydrofuran (THF, 10 mL), cooled to 0 °C, and then methylmagnesium bromide (MeMgBr, 0.75 mL, 3.0 M Et₂O, 2.22 mmol) was added dropwise. The reaction mixture was stirred for 6 hours. After the reaction was completed with saturated ammonium chloride aqueous solution, the mixture was extracted twice with ethyl acetate. The resulting organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure. The residue was purified by silica gel column chromatography to give the desired compound D8 (185 mg, 66% yield).

[0636] 1H NMR(500 MHz, CDCl3) δ 5.39 - 5.32(m, 1H), 5.18(t, J = 7.1 Hz, 1H), 4.74 - 4.69(m, 1H), 3.96 - 3.88(m, 1H), 3.57 - 3.45(m, 2H), 2.39 - 2.30(m,2H), 2.08 - 1.95(m, 2H), 1.93 - 1.76(m, 5H), 1.75 - 1.51(m, 12H), 1.50 - 1.38(m, 7H), 1.28 - 1.24(m, 1H), 1.21(s, 6H), 1.20 - 1.12(m, 3H), 1.11 - 1.03(m,2H), 1.01(s, 3H), 0.99 - 0.91(m, 1H), 0.55(s, 3H).

[0637] Synthesis Examples D9 and D10: Synthetic Examples D9 and D10 were prepared according to General Method 2.

[0638] Synthesis Examples D13 and D14: Synthetic Examples D13 and D14 were prepared according to General Method 3b.

[0639] The structures of synthetic examples 4-1 to 4-7 are shown in Table 14 below.

[0640] Table 14.

[0641]

[0642] Table 15 below lists the compound names and analytical data of the synthesis examples.

[0643] Table 15.

[0644]

[0645]

[0646]

[0647] Example 5:

[0648] Option 5-1

[0649]

[0650] Example 5-1 was prepared according to scheme 5.

[0651] Synthesis Example E1 was prepared according to General Method 1, and Synthesis Examples E2 and E3 were prepared as follows.

[0652] Synthetic Example E2: (E)-3-((3S,8S,9S,10R,13S,14S,17R)-10,13-dimethyl-3-((tetramethyl-3- ... 2H-pyran-2-yl)oxy)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecano-1H-cyclopentanol[a] ]Phenylacetyl-17-yl)but-2-enal

[0653] Synthetic Example E1 (333.0 mg, 0.78 mmol) was dissolved in dichloromethane (DCM, 33 mL), and Dess-Martin periodinane (DMP, 362.4 mg, 0.85 mmol) was added at 0 °C. The reaction mixture was then stirred at ambient temperature for 1 hour. After the reaction was complete with water, the mixture was extracted twice with dichloromethane. The resulting organic layer was dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure. The residue was purified by silica gel column chromatography to give the desired compound E2 (262.7 mg, 79% yield). 1 H NMR(500 MHz, CDCl3) δ 10.07(d, J = 7.9Hz, 1H), 5.93(dq, J1 = 8.0 Hz, J2= 1.2 Hz, 1H), 5.36-5.33(m, 1H), 4.72(dd, J1= 5.0 Hz, J2 = 2.8 Hz, 1H), 3.89 - 3.84(m, 1H), 3.59 - 3.41(m, 3H), 2.32 -2.37(m, 2H), 2.27 - 2.16(m, 5H), 2.08 - 1.95(m, 2H), 1.94 - 1.79(m, 6H), 1.79- 1.67(m, 4H), 1.66 - 1.37(m, 14H), 1.35 - 1.23(m, 3H), 1.22 - 1.16(m,1H), 1.12 - 1.04(m, 1H), 1.03 - 0.91(m, 6H), 0.62(s, 3H).

[0654] Synthetic Example E3: (3S, 8S, 9S, 10R, 13S, 14S, 17R)-17- ((2E, 4E)-7-methoxyheptane-2, 4-Dien-2-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecano-1H-cyclopentane [a]phenanthrene-3-ol

[0655] (3-Methoxypropyl)triphenylphosphonium bromide (237.5 mg, 0.57 mmol) was dissolved in tetrahydrofuran (THF, 29 mL), and sodium hydride (NaH, 45.8 mg, 1.14 mmol) was added at 0 °C. The reaction mixture was stirred at ambient temperature for 40 minutes. Synthetic Example E2 (122 mg, 0.29 mmol) was added dropwise at 0 °C, and the reaction mixture was stirred at ambient temperature for 3 hours. After the reaction with saturated ammonium chloride aqueous solution was complete, the mixture was extracted with ethyl acetate and washed with brine. The resulting organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was then distilled under reduced pressure. The residue was purified by silica gel column chromatography to give the desired compound E3 (27.4 mg, 20% yield).

[0656] 1 H NMR(500 MHz, CDCl3) δ 6.34(tt, J1 = 10.9 Hz, J2 = 1.7 Hz, 1H), 6.12(dq, J1 = 11.3 Hz, J2 = 1.3 Hz, 1H), 5.40 - 5.31(m, 2H), 4.72(dd, J1 = 5.0 Hz,J2 = 2.7 Hz, 1H), 3.89 - 3.84(m, 1H), 3.58 - 3.45(m, 2H), 3.43(td, J1 = 7.0Hz, J2 = 2.1 Hz, 2H), 3.35(d, J = 1.4 Hz, 3H), 2.47(qd, J1 = 7.1 Hz, J2 = 1.6Hz, 2H), 2.42 - 2.30(m, 2H), 2.26 - 2.14(m, 1H), 2.12(t, J = 9.2 Hz, 1H), 2.03 - 1.97(m, 1H), 1.94 - 1.79(m, 5H), 1.77(d, J = 1.3 Hz, 3H), 1.74 - 1.65(m, 3H), 1.63(s, 1H), 1.61 - 1.49(m, 7H), 1.49 - 1.38(m, 2H), 1.28 - 1.17(m,2H), 1.15 - 1.03(m, 2H), 1.01(d, J = 4.0 Hz, 3H), 0.99 - 0.93 (m, 1H), 0.57 (s, 3H).

[0657] Synthetic Example E4: (3S, 8S, 9S, 10R, 13S, 14S, 17R)-17-((2E, 4E)-7-methoxyheptane-2, 4-Dien-2-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecano-1H-cyclopentane [a]phenanthrene-3-ol

[0658] Synthesis Example E4 was prepared according to General Method 3b.

[0659] 1 H NMR (500 MHz, CDCl3) δ5.35 - 5.33 (m, 1H), 5.18 - 5.15 (m, 1H), 3.55 -3.48 (m, 1H), 3.36 (t, J = 7.5 Hz, 2H), 3.32 (s, 3H), 2.28 - 2.22 (m,4H), 2.06 - 1.96 (m, 4H), 1.85 - 1.77 (m, 4H), 1.62 - 1.37 (m, 15H), 1.19 -1.04 (m, 4H), 1.00 (s, 3H), 0.97 - 0.93 (m, 1H), 0.53 (s, 3H)

[0660] Synthetic Example 5-1: ((2R,3S)-3-acetoxy-6- (((3S,8S,9S,10R,13S,14S,17R)- 17- ((2E,4E)-7-methoxyheptane-2,4-dien-2-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12, 13,14,15,16,17-Tetradecano-1H-cyclopentan[a]phenanthrene-3-yl)oxy)-3,6-dihydro-2H-pyran-2-yl)acetic acid methyl ester

[0661]

[0662] 11H NMR (500 MHz, CDCl3) δ 6.37 - 6.32 (m, 1H), 5.93 - 5.79 (m, 3H), 5.58 (dt, J1 = 14.6 Hz, J2 = 7.1 Hz, 1H), 5.39 - 5.32 (m, 2H), 5.31 - 5.28 (m, 1H), 5.20 - 5.14 (m, 1H), 4.30 - 4.24 (m, 1H), 4.23 (d, J = 5.8 Hz, 1H), 4.21 - 4.15 (m, 2H), 3.60 - 3.51 (m, 1H), 3.43 (td, J1 = 6.9 Hz, J2 = 3.8 Hz, 3H), 3.35 (s, 1H), 3.35 (s, 3H), 2.50 - 2.44 (m, 1H), 2.42 - 2.32 (m, 5H), 2.10 (s, 3H), 2.08 (s, 1H), 2.08 (s, 4H), 1.92 - 1.79 (m, 6H), 1.77 (dd, J1 = 4.1 Hz, J2 = 1.2 Hz, 4H), 1.72 - 1.61 (m, 4H), 1.55 (d, J = 17.9 Hz, 11H), 1.49 - 1.37 (m, 3H), 1.26 (s, 5H), 1.20 (td, J1 = 12.4 Hz, J2 = 6.4 Hz, 3H), 1.13 - 1.02 (m, 1H), 1.00 (s, 5H), 0.99 - 0.92 (m, 2H), 0.92 - 0.83 (m, 2H), 0.58 (s, 1H), 0.57 (s, 3H).

[0663] Scheme 5-2

[0664]

[0665] Synthetic Example E5: (2E,4E)-5- ((3S,8S,9S,10R,13S,14S,17R)-10,13-dimethyl-3- ((tetrahydro-2H-pyran-2-yl)oxy)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecano-1H-cyclopentane [a] phenanthrene-17-yl)hex-2,4-dienoic acid methyl ester

[0666] Trimethyl phosphonoacetate (0.18 mL, 1.1 mmol) was added to THF (3 mL), cooled to 0 °C, and then n-butyllithium (1.1 mL, 1 M THF solution) was added at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. Synthetic Example E2 (158.0 mg, 0.30 mmol) was dissolved in THF (5 mL), and then slowly added to the mixture at 0 °C, while stirring the reaction mixture for 1 hour. After the reaction was completed with water, the reaction mixture was extracted twice with ethyl acetate. The resulting organic layer was dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure. The residue was purified by silica gel column chromatography to give the desired compound E5 (158.0 mg, 88.4% yield). 1 H NMR(500 MHz, CDCl3) δ 7.63 (ddd, J1 = 23.2, J2= 15.1,J3 = 11.6 Hz, 1H), 6.04 (dq, J1 = 11.5, J2 = 1.1 Hz, 1H), 5.80 (dd, J1 = 15.1,J2 = 3.5 Hz, 1H), 5.35 (ddt, J1 = 7.6, J2 = 5.5, J3 = 1.8 Hz, 1H), 4.72 (dd, J1= 4.9, J2 = 2.7 Hz, 1H), 3.95 - 3.86 (m, 1H), 3.74 (s, 4H), 3.57 - 3.43 (m,2H), 2.42 - 2.29 (m, 2H), 2.26 - 2.12 (m, 2H), 2.00 (dtd, J1 = 17.2, J2 = 5.2,J3 = 2.5 Hz, 2H), 1.92 (d, J = 1.2 Hz, 3H), 1.91 - 1.76 (m, 7H), 1.71 (ddq, J1= 12.7, J2 = 8.6, 4.3 Hz, 4H), 1.64 - 1.49 (m, 9H), 1.49 - 1.38 (m, 3H), 1.31- 1.18 (m, 3H), 1.18 - 1.02 (m, 3H), 1.00 (d, J = 4.6 Hz, 4H), 0.98 - 0.91 (m, 1H), 0.89 (s, 1H), 0.57 (s, 3H).

[0667] Synthetic Example E6: (2E,4E)-5- ((3S,8S,9S,10R,13S,14S,17R)-10,13-dimethyl-3- ((tetrahydro-2H-pyran-2-yl)oxy)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecano-1H-cyclopentane [a]phenanthrene-17-yl)hex-2,4-dien-1-ol

[0668] Synthetic Example E6 was prepared according to General Method 1.

[0669] 1 H NMR(500 MHz, CDCl3) δ 6.55 (ddt, J1 = 15.1, J2 = 10.9, J3 = 1.4 Hz, 1H), 5.91 (d, J = 10.9 Hz, 1H), 5.75 (dt, J1 = 14.9, J2 = 6.1 Hz, 1H), 5.35(ddd, J1 = 7.5, J2 = 5.3, J3 = 2.8 Hz, 1H), 4.71 (q, J = 3.6 Hz, 1H), 4.20 (t,J = 4.5 Hz, 2H), 3.92 (ddt, J1 = 10.6, J2 = 7.1, J3 = 3.1 Hz, 1H), 3.59 - 3.42(m, 3H), 2.40 - 2.26 (m, 2H), 2.26 - 2.15 (m, 1H), 2.09 (q, J = 7.6 Hz, 1H), 1.99 (dtd, J1 = 17.1, J2 = 5.4, J3 = 2.6 Hz, 2H), 1.94 - 1.81 (m, 7H), 1.81 -1.78 (m, 4H), 1.77 (d, J = 1.1 Hz, 1H), 1.75 - 1.63 (m, 5H), 1.63 - 1.49 (m,12H), 1.49 - 1.38 (m, 3H), 1.33 (s, 1H), 1.30 - 1.16 (m, 4H), 1.09 (dtd, J1 =18.8, J2 = 7.9, J3 = 3.8 Hz, 3H), 1.01 (s, 4H), 0.96 (ddd, J1 = 12.2, J2 =10.9, J3 = 4.8 Hz, 1H), 0.57 (s, 3H).

[0670] Synthetic Example E7. 2-(((3S,8S,9S,10R,13S,14S,17R)-17-((2E,4E)-6-methoxy (hexa-2,4-dien-2-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecano- 1H-cyclopentan[α]phenanthrene-3-yl)oxy)tetrahydro-2H-pyran

[0671] Synthesis Example E7 was prepared according to General Method 2.

[0672] 1H NMR (500 MHz, CDCl3) δ 6.52 (ddt, J = 15.0, 10.9, 1.3 Hz, 1H), 5.89 (dd, J = 11.0, 1.7 Hz, 1H), 5.64 (dt, J = 15.0, 6.3 Hz, 1H), 5.33 (ddd, J =7.7, 5.4, 2.8 Hz, 2H), 4.70 (q, J = 2.6 Hz, 2H), 3.96 (dd, J = 6.3, 1.4 Hz, 3H), 3.90 (ddt, J = 10.6, 6.8, 3.3 Hz, 2H), 3.56 - 3.43 (m, 4H), 3.33 (s, 3H), 2.39 - 2.25 (m, 3H), 2.24 - 2.13 (m, 1H), 2.11 - 1.93 (m, 5H), 1.84 (d,J = 5.2 Hz, 3H), 1.83 - 1.71 (m, 11H), 1.71 - 1.50 (m, 20H), 1.50 - 1.35 (m,5H), 1.25 - 1.15 (m, 4H), 1.07 (ddd, J = 21.5, 13.2, 5.5 Hz, 4H), 1.01 - 0.90(m, 7H), 0.90 - 0.77 (m, 1H), 0.66 - 0.48 (m, 4H).

[0673] Synthetic Example E8: (3S, 8S, 9S, 10R, 13S, 14S, 17R)-17- ((2E, 4E)-6-methoxyhexa-2, 4-Dien-2-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecano-1H-cyclopentane [a]phenanthrene-3-ol

[0674] Synthesis Example E8 was prepared according to General Method 3b.

[0675] 1H NMR(500 MHz, CDCl3) δ 6.54 (ddt, J1 = 15.0, J2 = 10.7, J3 = 1.4 Hz,1H), 5.90 (d, J = 10.9 Hz, 1H), 5.66 (dt, J1 = 15.2, J2 = 6.4 Hz, 1H), 5.35(dt, J1 = 4.8, J2 = 2.2 Hz, 2H), 4.15 - 4.09 (m, 1H), 3.99 - 3.93 (m, 2H),3.57 - 3.46 (m, 2H), 3.40 (d, J = 0.8 Hz, 1H), 3.34 (d, J = 2.0 Hz, 4H), 2.34- 2.18 (m, 4H), 2.17 (s, 1H), 2.12 - 1.95 (m, 5H), 1.90 - 1.73 (m, 13H), 1.67(ddt, J1 = 13.1, J2 = 8.5, J3 = 4.2 Hz, 4H), 1.62 - 1.36 (m, 15H), 1.30 - 1.16(m, 6H), 1.14 - 1.03 (m, 4H), 1.01 (d, J = 2.1 Hz, 6H), 0.99 - 0.91 (m, 2H),0.91 - 0.85 (m, 1H), 0.57 (s, 3H)。

[0676] Synthetic Example 5-2: ((2R,3S,6S)-3-acetoxy-6- (((3S,8S,9S,10R,13S,14S,17R) -17- ((2E,4E)-6-methoxyhexa-2,4-dien-2-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12, 13,14,15,16,17-Tetradecano-1H-cyclopentan[a]phenanthrene-3-yl)oxy)-3,6-dihydro-2H-pyran-2-yl)acetic acid methyl ester

[0677] 1H NMR(500 MHz, CDCl3) δ 5.87 (d, J = 10.4 Hz, 1H), 5.84 - 5.78 (m,1H), 5.42 - 5.32 (m, 4H), 5.32 - 5.24 (m, 2H), 5.17 (s, 1H), 4.97 (d, J 3.40 (d, J = 0.9 Hz, 3H),2.45 - 2.29 (m, 3H), 2.25 - 2.16 (m, 3H), 2.09 (d, J = 7.5 Hz, 12H), 2.04 -1.95 (m, 5H), 1.93 - 1.78 (m, 6H), 1.78 (dd, J = 6.0, 1.2 Hz, 5H), 1.73 -1.59 (m, 9H), 1.56 (s, 26H), 1.28 (d, J = 28.3 Hz, 39H), 1.01 (s, 6H), 0.91 -0.84 (m, 7H), 0.59 (d, J = 10.4 Hz, 3H).

[0678] Experimental Example

[0679] Experimental preparation: Cell incubation

[0680] Human umbilical vein endothelial cells (HUVECs) were purchased from Innoprot (Innovative Technologies in Biological Systems, Spain) and incubated in 100 mm culture dishes containing ECM medium (ScienCell, USA) supplemented with 5% (w / v) fetal bovine serum (FBS, ScienCell, USA), 1% penicillin (ScienCell, USA), and 1% endothelial cell growth additive (ScienCell, USA). The cells were then cultured at 37°C in an incubator containing 5% CO2.

[0681] Experimental Example 1. Screening synthetic derivatives by measuring their inhibitory activity against vascular endothelial cell death.

[0682] To confirm the inhibitory activity of the synthetic derivative on vascular endothelial cell death, a screening experiment was conducted. Human umbilical vein endothelial cells (HUVECs) were screened at a concentration of 3 (±0.5) × 10⁶ cells / year. 4 Cells were seeded at a density of 10 cells / well in 24-well plates containing 500 μL of ECM medium (Sciencell, USA) supplemented with 5% fetal bovine serum (FBS). The next day, the cells were transferred to serum-free medium (SFM) containing compound 1 synthesized according to the above synthetic examples at a concentration of 10 μg / mL. Cell viability was assessed using an MTT assay after 48 hours, and the results are listed in Table 16.

[0683] Synthetic derivatives 1-3, 1-6, 1-13, 1-18, 1-20, 1-22, 1-23, 1-36, 3-13, 3-23, 4-1, 4-5, 4-6, and 4-7 showed inhibitory activity against cell death at a concentration of 1 μg / mL. Synthetic derivatives 1-2, 1-5, 1-9, 1-11, 1-12, 1-25, 1-33, 1-37, 1-44, 1-57, 3-3, 3-4, 3-5, 3-17, 3-19, 3-20, 4-3, 4-4, 5-1, and 5-2 showed inhibitory activity against cell death at a concentration of 10 μg / mL. Furthermore, synthetic derivatives 1-1, 1-4, 1-7, 1-8, 1-10, 1-14, 1-15, 1-17, 1-19, 1-30, 1-31, 1-34, 1-35, 1-42, 1-56, 2-3, 2-5, 2-6, 2-7, 3-6, 3-11, 3-12, 3-14, 3-16, and 4-4 all exhibited inhibitory activity against cell death at concentrations of 1 μg / mL and 10 μg / mL. Among the aforementioned synthetic derivatives, derivatives 1-4, 1-7, 1-8, 1-10, 1-14, 1-15, 1-17, 1-30, 1-31, 1-33, 1-34, 1-37, 2-3, 3-11, and 5-2 exhibited excellent inhibitory activity against cell death, and these inhibitory activities are as follows: Figures 1a to 1o As shown. Furthermore, morphological changes observed in treated vascular endothelial cells confirmed the protective effects of these derivatives on the cells. Cell morphological changes induced by each synthetic derivative are shown in... Figures 2a to 2o .

[0684] Table 16.

[0685]

[0686]

[0687]

[0688] Experimental Example 2. Confirmation of the Cell Protective Effect of Synthetic Derivatives

[0689] Based on the results of Experiment 1, the protective effects of synthetic derivatives 1-4, 1-7, 1-8, 1-10, 1-14, 1-15, 1-17, 1-30, 1-31, 1-33, 1-34, 1-37, 2-3, 3-11, and 5-2, which have inhibitory activity against cell death, on vascular endothelial cell membranes were further evaluated using concentration-dependent MTT and LDH analyses. Lactate dehydrogenase (LDH) is normally retained intracellularly and not released into the culture medium. However, LDH is released into the culture medium when the cell membrane is damaged or cells die. Furthermore, the amount of LDH present in the culture medium is proportional to the number of damaged or dead cells. Higher LDH levels indicate greater cell damage. Vascular endothelial cells were cultured at 5 × 10⁻⁶ cells / mL. 3 Cells were seeded at a density of 10 cells / well in 96-well plates and incubated for 24 hours. Each compound was diluted in SFM to final concentrations of 1, 5, and 10 μg / mL and added to the wells. After 48 hours of incubation, 30 μL of culture supernatant was reacted with 30 μL of LDH substrate solution (CytoTox 96 reagent, Promega) at room temperature for 30 minutes. To terminate the reaction, 30 μL of stop solution (Promega) was added, and absorbance was measured to evaluate membrane protection.

[0690] Synthetic derivatives 1-4, 1-7, 1-8, 1-10, 1-14, 1-15, 1-17, 1-30, 1-31, 1-33, 1-34, 1-37, 3-11, and 5-2 exhibited concentration-dependent inhibition of cell death and reduction of LDH release under serum-free conditions, confirming the cytoprotective effects of these compounds. Conversely, synthetic derivative 2-3 demonstrated concentration-dependent inhibition of cell death under serum-free conditions, but its LDH inhibition was most pronounced at 5 μg / mL. Figures 3a to 3o The inhibitory effects of synthetic derivatives 1-4, 1-7, 1-8, 1-10, 1-14, 1-15, 1-17, 1-30, 1-31, 1-33, 1-34, 1-37, 2-3, 3-11 and 5-2 on cell death were explained respectively. Figures 4a to 4o Data on the reduction in LDH release for each synthetic derivative are shown.

[0691] Experimental Example 3. Screening for synthetic derivatives based on changes in cell junction protein expression

[0692] Based on the results of Experiments 1 and 2, the synthetic derivatives 1-4, 1-7, 1-8, 1-10, 1-14, 1-15, 1-17, 1-30, 1-31, 1-33, 1-34, 1-37, 2-3, 3-11, and 5-2 were confirmed to enhance the survival of HUVECs under serum-free conditions. Furthermore, the ability of these derivatives to inhibit VEGF-induced destabilization of VE-cadherin was evaluated. Cadherins are known to play a crucial role in maintaining vascular integrity and are closely related to the permeability of vascular endothelial cells. To evaluate the inhibitory activity of the synthetic derivatives on changes in cell junction protein expression, a screening assay was performed. Fusion HUVECs were pretreated with the synthetic derivatives at a concentration of 5 μg / mL for 1 h, followed by treatment with VEGF (50 ng / mL, Biolegen, 718302) for 1 h. The cells were then fixed with 4% paraformaldehyde at room temperature for 20 min and washed three times with PBS (pH 7.4). Cells were permeabilized with 0.1% Triton X-100 PBS solution and washed three times. Cells were then reacted overnight with an antibody against VE-cadherin (Santa Cruz Biotechnology, Inc., SC-9989). The next day, cells were treated with a secondary antibody (Goatanti-Mouse IgG (H+L), Highly Cross-Adsorbed, Alexa Fluor® 594, Invitrogen, USA) and fixed for observation under a fluorescence microscope (Leica). Figure 5 To visualize the expression of junction proteins, backbone analysis was performed using Junction Mapper software. Figure 6 When quantifying the number of ligands (Nb fragments) and the total ligand length (fragment length), it was found that both parameters were reduced in the VEGF-treated group compared to the control group, while synthetic derivatives 1-4, 1-7, 1-8, 1-10, 1-14, 1-15, 1-17, 1-30, 1-31, 1-33, 1-34, 1-37, 2-3, 3-11, and 5-2 inhibited the destabilizing effect of VE-cadherin. Figure 7 and 8 The synthetic derivatives 1-10, 1-14, 1-17, 2-3, and 3-11 have been shown to have the most significant stabilizing effect on VE-cadherin.

[0693] Experimental Example 4. Confirmation of the inhibitory effect of synthetic derivatives on cell permeability

[0694] Based on the results of Experiment 3, the ability of synthetic derivatives 1-10, 1-14, 1-17, 2-3, and 3-11 to inhibit the destabilization of VE-cadherin was confirmed. To further confirm the inhibitory effect of these synthetic derivatives on cell permeability, transepithelial / transendothelial resistance (TEER) and FITC-glucan permeability measurements were performed. Vascular endothelial cells were subjected to a permeability assay of 5.0 (±1.0) ×10⁻⁶. 4 Cells were seeded at a density of 10 cells / well onto 1% gelatin-coated Transwells in 5% ECM medium and incubated for 2 days to form a confluent monolayer. After serum starvation for 2 hours in serum-free medium (SFM), cells were treated with synthetic derivatives 1-10, 1-14, 1-17, 2-3, and 3-11 at concentrations of 5 μg / mL for 1 hour. To induce permeability of the HEVES monolayer, VEGF (100 ng / mL) was applied for 45 minutes. Compared to the control group, increased cell permeability, resulting in decreased resistance across the endothelial barrier, was observed in the VEGF-treated groups. Conversely, in the co-treatment groups of VEGF and synthetic derivatives, the resistance across the endothelial barrier was significantly increased compared to the VEGF-only treatment group. Figures 9a to 9e Additionally, FITC leakage increased in the VEGF-treated group compared to the control group, while FITC leakage decreased in the co-treatment group with VEGF and synthetic derivatives compared to the VEGF-only treatment group. Figures 10a to 10e ).

[0695] Experiment Example 5: Confirmation of the effect of cognitive function enhancement

[0696] 1) Preparation for animal experiments

[0697] Three-month-old male 5xFAD transgenic (TG) mice were used as an Alzheimer's disease model, with age-matched wild-type (WT) mice serving as controls. Synthetic Examples 1-10, 2-3, and CU06-1004 were administered orally once daily at doses of 5, 10, and 20 mg / kg for 6 months.

[0698] A total of eight experimental groups were prepared, namely: 1) G1: WT + carrier; 2) G2: TG + carrier; 3) G3: TG + donepezil (1 mg / kg); 4) G4: TG + synthetic examples 1-10 (5 mg / kg); 5) G5: TG + synthetic examples 1-10 (10 mg / kg); 6) G6: TG + synthetic examples 1-10 (20 mg / kg); 7) G7: TG + CU06-1004 (10 mg / kg); and 8) G8: TG + synthetic examples 2-3 (10 mg / kg). After administering these synthetic derivatives and substances daily for 6 months, cognitive function and learning ability were evaluated using the Novel Object Recognition (NOR) test and the Morris Water Maze (MWM) test.

[0699] 2) Novel Object Recognition Test (NOR)

[0700] To assess the differences in exploration behavior between familiar and novel objects, a novel object recognition (NOR) test was conducted. Rodents such as mice typically exhibit curiosity when faced with two identical objects, leading to similar contact behaviors, exploration time, and frequency. When one object is replaced with a novel object, cognitively sound mice tend to show greater interest in the new object, resulting in longer exploration time and frequency. However, mice with impaired memory were unable to distinguish the novel object, and their exploration time and frequency did not show a significant increase. In this study, the G2 group (carrier) showed a significantly lower discrimination index compared to the G1 group, indicating significant cognitive impairment. Figure 11 Conversely, the G5 group (synthetic examples 1-10, 10-10 mg / kg) showed an increasing trend in discrimination index relative to the G2 group, indicating a potential improvement in cognitive function.

[0701] 3) Morris Water Maze (MWM) Experiment

[0702] To evaluate spatial learning and memory abilities, a Morris water maze apparatus was used to train mice to memorize the positions of platforms in a water tank for five days. During training, mice swam to find the platforms to avoid drowning, and through repeated trials, the mice learned and remembered the platform positions. On the sixth day, the platforms were removed to assess whether the mice had remembered their positions.

[0703] In this trial, the G2 group spent approximately 30% less time near the platform location than the G1 group, indicating impaired cognitive function. Figure 12Conversely, group G5 showed a significant increase of approximately 30% in memory retention and time spent near the plateau compared to group G2. Furthermore, group G5 exhibited impaired memory performance comparable to group G1, confirming that administration of synthetic examples 1-10 at 10 mg / kg effectively enhanced long-term memory capacity. 4) Results

[0704] The compound according to the invention (10 mg / kg) exhibited cognitive and memory-enhancing effects in both the Novel Object Recognition (NOR) test and the Morris Water Maze (MWM) test. Therefore, although amyloid-β (Aβ) is a contributing factor to Alzheimer's disease, this compound shows protective effects on neurons in the brain, thus offering a therapeutic potential for neurodegenerative diseases such as Alzheimer's disease.

[0705] Experimental Example 6. Analysis of factors associated with neurodegenerative diseases

[0706] 1) Immunohistochemical staining methods

[0707] After the behavioral experiment, mice were anesthetized and perfused with 0.9% saline, then fixed with 4% paraformaldehyde. Brain tissue was then extracted and post-fixed by immersion in 4% paraformaldehyde at 4°C, followed by storage in PBS containing 0.02% sodium azide. The brain tissue was frozen and sectioned at a thickness of 20 μm. Sections were stored in storage buffer at 4°C until use. For immunostaining, sections were washed with PBS and incubated at room temperature for 1 hour in a blocking solution containing PBS, 5% normal goat serum, and 0.3% Triton X-100. Brain sections from the prefrontal cortex and hippocampus of the cerebral hemispheres were incubated overnight with primary antibodies at 4°C. The next day, sections were washed with PBS and incubated with secondary antibodies at room temperature for 1 hour. After washing with PBS, sections were air-dried and mounted with a mounting medium containing DAPI. The stained sections were then observed and imaged using confocal microscopy.

[0708] 2) Western blot analysis

[0709] Following transcranial perfusion of mice with 0.9% saline, brain tissue was harvested and immediately flash-frozen in liquid nitrogen. Brain samples were stored at -80°C until analysis. For protein extraction, brain tissue was homogenized in a radioimmunoprecipitation assay (RIPA) buffer containing protease and phosphatase inhibitors, wherein the buffer composition consisted of: 0.5% NP-40, 50 mM β-glycerophosphate, 0.5% NaF, 50 mM Na3VO4, 1% Triton X-100, 0.5% sodium deoxycholate, 1 M Tris-HCl, 50 mM NaCl, and 5 mM EDTA. The homogenate was centrifuged at 12,000 × g for 15 min at 4°C, and protein concentration was determined using the bicinconinic acid (BCA) method and the SMART BCA assay kit (Intron Biotechnology, Korea). Proteins were separated by 8–12% SDS-PAGE and transferred to a polyvinylidene fluoride (PVDF) membrane. The membrane was blocked with 3% bovine serum albumin (BSA) and incubated overnight at 4°C with primary antibody and 3% BSA. The next day, the membrane was incubated with secondary antibody for 1 hour. Protein bands were visualized using a Geldoc XR imaging system (Bio-Rad), and band intensity was imaged and quantified using ImageJ software.

[0710] 3) Confirmation of amyloid-β (Aβ) expression levels

[0711] After verifying the cognitive enhancement effects of the compounds according to this disclosure, the effects of the compounds according to the invention on amyloid β (Aβ) plaque accumulation were investigated by immunohistochemical staining of the hippocampus and cerebral cortex of the brain.

[0712] In the hippocampus, Aβ plaque accumulation was assessed using the 6E10 antibody (anti-amyloid β). Figure 13a and 13b As shown, group G2 showed a significant increase in 6E10 signal intensity compared to group G1, while groups (G4, G5, G6, G7, and G8) treated with synthetic examples 1-10, CU06-1004, and synthetic examples 2-3 showed a significant reduction in Aβ plaque accumulation compared to group G2 (TG + excipient).

[0713] In the cerebral cortex, the accumulation of β-amyloid (Aβ) in groups G4, G5, G6, and G7, which received synthetic examples 1-10 and CU06-1004, was significantly reduced compared to group G2 (TG + carrier). Notably, groups G4 and G5, treated with synthetic examples 1-10 at doses of 5 and 10 mg / kg, respectively, showed a more significant reduction in amyloid β (Aβ) plaque accumulation. Figure 13c and 13d ).

[0714] These results demonstrate that the compounds of the present invention effectively reduce the accumulation of β-amyloid (Aβ) plaques in a 5xFAD transgenic mouse model of Alzheimer's disease.

[0715] 4) Confirmation of the expression level of vascular endothelial cell junction proteins

[0716] The blood-brain barrier (BBB) ​​in cerebral vascular tissue is a specialized structure located between the vascular system and the brain parenchyma, maintained by tight junctions and adhesion junctions between microvascular endothelial cells. It plays a crucial role in preventing blood leakage into the brain. These endothelial cells are surrounded by pericytes, astrocytes, neurons, and extracellular matrix components, further enhancing the structural integrity of the BBB. Due to this structure, the BBB not only regulates the transport of nutrients from the bloodstream to the brain but also controls the migration of immune cells, thereby maintaining the homeostasis of the central nervous system (CNS). However, in neurodegenerative diseases such as Alzheimer's disease, tight junctions weaken and are disrupted, leading to leakage of blood components and immune cells into the brain parenchyma, resulting in neuronal damage. To evaluate the protective effect of the compounds of this invention on the BBB in a 5xFAD Alzheimer's disease model, the expression levels of the connexins ZO-1 and Claudin-5 were analyzed.

[0717] Immunohistochemical staining and Western blot analysis showed that, based on changes in connexin expression levels, ZO-1 expression levels were significantly lower in the G2 group (5xFAD model) compared to the G1 group. Conversely, the G5 group (synthetic examples 1-10, 10-10 mg / kg) showed a significantly increased ZO-1 expression level compared to the G2 group. Figures 14a-14c ).

[0718] Similarly, compared to group G1, the change in Claudin-5 expression level in group G2 (5xFAD model) was significantly reduced. However, compared to group G2, the Claudin-5 expression level in groups G6 (synthetic examples 1-10, 20 mg / kg), G7 (CU06-1004), and G8 (synthetic examples 2-3) was significantly increased. Figure 14d and 14e Furthermore, as confirmed by staining for laminin (a component of the ECM surrounding blood vessels), the vascular morphology was maintained, indicating structural maintenance of the vascular system.

[0719] These results demonstrate that the compounds of the present invention effectively treat Alzheimer's disease models and can be used as a novel treatment for Alzheimer's disease.

[0720] 5) Confirmation of blood-brain barrier transporter expression levels

[0721] Since the compounds of this invention showed reduced amyloid-β (Aβ) accumulation and increased the expression levels of connexins in vascular endothelial cells in a 5xFAD transgenic mouse model of Alzheimer's disease, the expression levels of blood-brain barrier (BBB) ​​influx transporters and receptor for advanced glycation end products (RAGE) were subsequently evaluated. RAGE is a multi-ligand receptor involved in the pathogenesis of inflammatory diseases, diabetic complications, and Alzheimer's disease. It promotes the transport of circulating β-amyloid protein (Aβ) across the BBB into the brain, thereby promoting oxidative stress, inflammatory responses, and reduced cerebral blood flow, accelerating the progression of Alzheimer's disease.

[0722] Western blot analysis revealed that RAGE expression levels were significantly increased in group G2 (5xFAD model) compared to group G1. Conversely, RAGE expression levels were significantly decreased in groups G4, G5, and G6 treated with synthetic examples 1-10 at doses of 5, 10, and 20 mg / kg, respectively, and in groups G7 and G8 treated with CU06-1004 and synthetic examples 2-3, respectively. Figure 15a and 15b ).

[0723] Experimental Example 7. Confirmation of Anti-Neuroinflammatory Effect

[0724] 1) Confirmation of the inhibitory effect on astrocyte hyperactivation

[0725] To evaluate whether the reduction in β-amyloid (Aβ) accumulation by the compounds of this invention is related to their anti-neuroinflammatory effect in the 5xFAD transgenic mouse model of Alzheimer's disease, immunofluorescence staining and Western blot analysis were performed using glial cell fibrillary acidic protein (GFAP) antibody (a marker of astrocytes), as described in Experimental Example 2.

[0726] Immunofluorescence staining and Western blot analysis showed that GFAP expression levels were significantly increased in group G2 (5xFAD model) compared to group G1. Conversely, GFAP expression levels were significantly decreased in groups G5 and G6, treated with synthetic samples 1-10 at doses of 10 and 20 mg / kg, respectively. Figure 16a and 16b Furthermore, white matter blot analysis showed a significant increase in GFAP expression levels in group G2 compared to group G1, while all treatment groups, including those treated with synthetic examples 1-10, CU06-1004, and synthetic examples 2-3, showed a significant decrease in GFAP expression levels. Figure 16c and 16d ).

[0727] These findings demonstrate that the compounds of the present invention effectively inhibit the hyperactivation of astrocytes in Alzheimer's disease-induced neuroinflammatory symptoms.

[0728] 2) Confirmation of its inhibitory effect on microglia hyperactivation

[0729] Microglia in the brain act as macrophages responsible for immune function. They maintain central nervous system homeostasis by engulfing misfolded proteins, cell debris, and dead cells. Therefore, to evaluate the microglia-mediated anti-neuroinflammatory effects of the compounds of the present invention in a 5xFAD transgenic mouse model of Alzheimer's disease, immunofluorescence staining was performed using an antibody against Iba1, a marker of microglia activation, as described in Example 2.

[0730] Analysis showed that, compared with group G1, Iba1 expression level was significantly increased in group G2 (5xFAD model), while Iba1 expression level was significantly decreased in groups G4, G5, and G6 treated with synthetic examples 1-10 at doses of 5, 10, and 20 mg / kg, respectively, and in groups G7 (CU06-1004) and G8 (synthetic examples 2-3). Figure 17a and 17b ).

[0731] These results demonstrate that the compounds of the present invention effectively inhibit chronic microglial activation in an Alzheimer's disease model, thereby achieving an anti-neuroinflammatory effect.

[0732] Experiment Example 8: Determination of Solubility

[0733] 1) Measurement of solubility in water

[0734] Excess amounts of Synthetic Examples 2-3, Synthetic Examples 1-10, and CU06-1004 (1-2 mg) (theoretical concentration: approximately 1 mg / mL) were added to water (FDDW) and vortexed thoroughly. The mixture was incubated at 25°C with stirring at 200 rpm for 48 hours. After incubation, the sample was centrifuged at 14,000 rpm for 15 minutes, and the supernatant was collected and filtered through a 0.2 μm syringe filter. The filtrate was diluted with two volumes of methanol or methanol containing an internal standard (IS) and quantitatively analyzed using UPLC-DAD or LC-MS / MS.

[0735] HPLC-DAD conditions:

[0736] - Instrument: Agilent HPLC 1260

[0737] - Column: Synergi Polar RP (150mm × 2.0mm inner diameter, 4μm)

[0738] - Mobile phase: 0.1% formic acid: acetonitrile (10:90)

[0739] -UV wavelength: 234 nm (Compounds B, C)

[0740] - Flow rate: 0.2 mL / min

[0741] - Injection volume: 5μL

[0742] -Total running time: 7 minutes

[0743] LC-MS / MS conditions:

[0744] - Instrument: Agilent HPLC 1290 Infinity II–AB SCIEX 3500 tandem mass spectrometer

[0745] - Column: Synergi Polar RP (150mm × 2.0mm inner diameter, 4μm)

[0746] -Mobile phase: 0.1% formic acid:acetonitrile (30:70)

[0747] - Flow rate: 0.3 mL / min

[0748] -Injection volume: 2μL

[0749] -Total running time: 8 minutes

[0750] -MRM condition (m / z): 695.213 → 186.9

[0751] -IS: Phenacetin (100ng / mL)

[0752] result

[0753] The compounds from Synthetic Examples 2-3 exhibited high water solubility of 106 μg / mL. In contrast, the compounds from Synthetic Examples 1-10 and CU06-1004 showed solubility levels below the quantitation limit, indicating that the compounds from Synthetic Examples 1-10 and CU06-1004 exhibited poor solubility in water.

[0754] Table 17

[0755] .

Claims

1. Compounds with the following chemical formulas IA, IB, IC, ID, IE, IF, IG, IH, or IJ, and their stereochemical properties. Isomers or pharmaceutically acceptable salts: The dashed lines represent single bonds or bonds that do not exist. Y represents H and C. 1-6 Alkyl, -C (= O) (R 1 ) or -P (=O) (R 2 ) (R 3 ); R 1 To R 3 Each independently is C 1-6 Alkyl or phenyl; X is H or C 1-6 alkyl; R is -C n alkylene-L-M-R 4 ; n is an integer from 0 to 10, and -C n Alkyl groups may optionally contain carbon-carbon double bonds; L is C (= O) or CH2; M represents O, S, N (R) 5 (or does not exist;) R 4 C is H, unsubstituted, or substituted with one or more halogens. 1-6 Alkyl, unsubstituted 3 to 10 nucleotides Cycloalkyl or one or more halogen-substituted 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocycloalkyl, -C(=O)(R 6 ) or -S (= O)2(R 7 ); R 5 For H or C 1-6 alkyl; R 6 and R 7 Each independently is C 1-6 alkyl; V is H or C 1-6 Alkyl, under the condition that This compound is not .

2. The compounds of formula IA, IB, IC, ID, IE, IF, IG, IH or IJ as described in claim 1. The substance, its stereoisomers or pharmaceutically acceptable salts, of which Y represents H and C. 1-6 Alkyl, -C (= O) (R 1 ) or -P (= O) (R 2 ) (R 3 ); R 1 To R 3 Each independently is C 1-6 alkyl; X is H or C 1-6 alkyl; R is -C n Alkylene-LMR 4 ; n is an integer between 0 and 10; L is CH2; M represents O, S, N (R) 5 (or does not exist;) R 4 C is H, unsubstituted, or substituted with one or more halogens. 1-6 Alkyl, unsubstituted 3 to 10 nucleotides Cycloalkyl or one or more halogen-substituted 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocycloalkyl, -C(=O)(R 6 ) or -S (= O)2(R 7 ); R 5 For H or C 1-6 alkyl; R 6 and R 7 Each independently is C 1-6 alkyl; V is H or C 1-6 alkyl.

3. The compound of formula IA or IE as described in claim 1, its stereoisomers, or pharmaceutically acceptable compounds. The salt received, of which Y is -C (= O) (R) 1 ); R 1 C 1-6 alkyl; X is H or C 1-6 alkyl; R is -C n Alkylene-LMR 4 ; n is an integer between 0 and 10; L is CH2; M represents O, S, N (R) 5 (or does not exist;) R 4 C is either unsubstituted or substituted with one or more halogens. 1-6 Alkyl, unsubstituted 3 to 10 Cycloalkyl, or 6- to 10-membered aryl, 5- to 10-membered heteroaryl, -C (= O)(R) substituted with one or more halogens 6 ) or -S (= O)2(R 7 ); R 5 For H or C 1-6 alkyl; R 6 and R 7 Each independently is C 1-6 alkyl.

4. The compound of formula IA or IE as described in claim 1, its stereoisomers, or pharmaceutically acceptable compounds. The salt received, of which Y is -C (= O) (R) 1 ); R 1 C 1-6 alkyl; X is H or C 1-6 alkyl; R is -C n Alkylene-LMR 4 ; n is an integer between 0 and 10; L is CH2; M is O; R 4 C is either unsubstituted or substituted with one or more halogens. 1-6 Alkyl, unsubstituted 3- to 10- Cycloalkyl, or 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocyclic aryl, -C (= O)(R) substituted with one or more halogens 6 ) or -S (= O)2(R 7 ); R 6 and R 7 Each independently is C 1-6 alkyl.

5. The compound of formula IA as claimed in claim 1, its stereoisomers, or pharmaceutically acceptable compounds. Salt, of which Y is -C (= O) (R) 1 ); R 1 C 1-6 alkyl; X is C 1-6 alkyl; R is -C n Alkylene-LMR 4 ; n is an integer between 0 and 10; L is CH2; M is O; R 4 C 1-6 alkyl.

6. A compound of formula IA as claimed in claim 1, its stereoisomers, or a pharmaceutically acceptable compound. Salt, of which Y is -P (= O) (R) 2 ) (R 3 ); R 1 To R 3 Each is independently a C1–6 alkyl or phenyl group; X is C 1-6 alkyl; R is -C n Alkylene-LMR 4 ; n is an integer between 0 and 10; L is C (= O); M is O; R 4 C 1-6 alkyl.

7. A compound of formula IA as claimed in claim 1, its stereoisomers, or a pharmaceutically acceptable compound. Salt, of which Y is -P (= O) (R) 2 ) (R 3 ); R 1 To R 3 Each independently is C 1-6 alkyl; X is C 1-6 alkyl; R is -C n Alkylene-LMR 4 ; n is an integer between 0 and 5; L is C (= O); M is O; R 4 C 1-6 alkyl.

8. A compound of formula IA as claimed in claim 1, its stereoisomers, or a pharmaceutically acceptable compound. Salt, of which Y is -C (= O) (R) 1 ); R 1 C 1-6 alkyl; X is C 1-6 alkyl; R is -C n Alkylene-LMR 4 ; n is an integer between 0 and 5; L is CH2; M is O; R 4 C 1-6 alkyl.

9. The compound of the following formula as claimed in claim 1, its stereoisomer, or a pharmaceutically acceptable salt thereof: 。 10. A pharmaceutical composition for the prevention or treatment of vascular endothelial dysfunction, wherein the composition... The product contains the compound of claim 1, its stereoisomer, solvate, hydrate or pharmaceutically acceptable salt as the active ingredient.

11. The pharmaceutical composition for the prevention or treatment of vascular endothelial dysfunction as described in claim 10, The endothelial dysfunction mentioned above is associated with vascular leakage diseases.

12. The pharmaceutical composition for the prevention or treatment of vascular endothelial dysfunction as described in claim 10, The vascular endothelial dysfunction mentioned therein includes diabetes, inflammation, retinopathy, diabetic retinopathy, macular degeneration, glaucoma, stenosis, restenosis, arteriosclerosis, atherosclerosis, cerebral edema, arthritis, arthropathy, uveitis, inflammatory bowel disease, macular edema, cancer, hyperlipidemia, ischemic disease, diabetic foot ulcer, pulmonary hypertension, acute lung injury, myocardial ischemia, heart failure, acute limb ischemia, myocardial infarction, stroke, ischemia or reperfusion injury, vascular leakage syndrome (VLS), edema, transplant rejection, burns, acute or adult respiratory distress syndrome (ARDS), sepsis, or autoimmune diseases.

13. A method for treating vascular endothelial dysfunction, wherein the method includes administering medication to a recipient in need. The test subject administers a therapeutically effective amount of the compound as described in claim 1, its stereoisomers, or a pharmaceutically acceptable salt.

14. The compound of claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, used for For the preparation of drugs to prevent or treat vascular endothelial dysfunction.

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